Dimethyl fumarate particles and pharmaceutical compositions thereof

ABSTRACT

The present invention provides dimethyl fumarate (DMF) particles and methods of preparing the DMF particles. Also provided is DMF coated particles comprising DMF particles coated with an enteric coating. The invention also provides various dosage forms and methods of treating a disease or disorder (e.g., multiple sclerosis).

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/737,011, filed Dec. 15, 2017, which is a 371 National StageApplication of International Application No.: PCT/US2016/037486, filedJun. 15, 2016, which claims the benefit of the filing date, under 35U.S.C. § 119(e), of U.S. Provisional Application No. 62/181,061, filedJun. 17, 2015. The entire contents of each of the foregoingapplications, including all drawings, formulae, specification, andclaims, are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention generally relates to dimethyl fumarate particles,pharmaceutical compositions and uses thereof.

BACKGROUND OF THE INVENTION

TECFIDERA™ has been approved by the U.S. Food and Drug Administrationfor the treatment of patients with relapsing forms of multiple sclerosis(MS). TECFIDERA™ contains dimethyl fumarate (DMF), which has thefollowing structure:

The starting dose for TECFIDERA™ is 120 mg twice a day orally. After 7days, the dose is to be increased to the maintenance dose of 240 mgtwice a day orally. TECFIDERA™ can be taken with or without food.

There is currently no FDA approved once a day dosing regimen, i.e., QDdosing, for DMF. One objective of the present invention is to develop aformulation (e.g., a unit dosage form) that is suitable for once a daydosing.

In addition, dimethyl fumarate (DMF) isolated from the current chemicalsynthesis needs to undergo a particle size reduction using a jet-millingprocess prior to drug product manufacturing. The reduced particlesobtained by jet milling process have shown at times poor processabilityduring drug product manufacture due to particle to particlecohesiveness.

Dimethyl fumarate also poses peculiar physical properties such assublimation, low minimum ignition energy (MIE) and sensitizing effectsso that the handling of this compound requires careful and at timestedious procedures to avoid employee exposures and ensure process safety(to avoid potential dust explosion.)

Therefore, there is a need for DMF particles with desirable bulk solidproperties and manufacturing processability as well new processes forpreparing such DMF particles with minimized safety risk.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides pharmaceuticalformulations (e.g., unit dosage forms) that are suitable for once a daydosing with DMF. The once a day formulations or unit dosage forms of thepresent invention are believed to have similar pharmacokinetic profileas the current FDA approved twice a day dosing regimen. In certainembodiments, the once a day unit dosage forms comprise two dosagecomponents. Upon oral administration, the first dosage componentprovides a first immediate dose of DMF. The second dosage component isretained in stomach for a prolonged period of time, providing a delayedrelease of a second dose of DMF. Alternatively, the first dosagecomponent is retained in the stomach and provides a delayed immediatedose of DMF; while the second dosage component is also retained instomach for a prolonged period of time and provides a prolongedcontrolled release of a second dose of DMF. In certain embodiments, thepresent formulations or unit dosage forms can also improve DMFabsorption into the blood stream.

It is known that DMF may cause gastrointestinal side-effects, such asnausea, vomiting and diarrhea. To minimize these GI side-effects, it isdesirable that the unit dosage form of the present invention does notrelease significant amounts of DMF in stomach. Particularly, as thesecond dosage form and in some embodiments the first dosage form isretained in the stomach for a prolonged period time, it is essential tominimize the amount of DMF released when the dosage component isretained in the stomach. This objective is achieved by theenterically-coated DMF particles of the present invention. In certainembodiments, the enterically coated DMF particles of the presentinvention release no more than 20% DMF for 4 to 12 hours when subjectedto an in vitro dissolution test employing USP Simulated Gastric Fluid(SGF) without pepsin as dissolution medium.

In another aspect, the present invention also provides DMF particleshaving desirable particle size, powder properties and morphology,suitable as starting material for preparing the enterically coated DMFparticles of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows flow measurements of drug product blend containingwet-milled dimethyl fumarate using Flodex. The y-axis indicates theaperture of cone containing the blend powder. Smaller aperture indicatesbetter flow.

FIG. 2 shows particle images for wet-milled dimethyl fumarate andjet-milled dimethyl fumarate.

FIG. 3 shows various morphology properties for wet-milled DMF andjet-milled DMF.

FIG. 4 shows SEM images for uncoated DMF particles and entericallycoated DMF particles.

FIG. 5 shows DMF release profile for coated DMF particles in SimulatedGastric Fluid (SGF).

FIG. 6 shows DMF release profile for coated DMF particles of the presentinvention in Simulated Intestine Fluid (SIF).

FIG. 7A shows SEM images of unmilled coarse DMF; FIG. 7B shows SEM imageof wet-milled DMF; FIG. 7C shows SEM images of coated DMF particlesusing unmilled coarse DMF; while FIG. 7D shows SEM images of coated DMFparticles using wet-milled DMF of the present invention.

FIGS. 8A and 8B show a design of a delayed release tablet formulation.FIG. 8A shows a design of a coated delayed releaseminitablet/microtablet which contains a core tablet matrix, a sealcoating layer, a semipermeable coating layer, and a pH7 release coatinglayer. FIG. 8B shows a picture and a microscopic view of a delayedrelease tablet having three coating layers: an inner seal coating layer,a semipermeable coating layer, and an outer pH 7 release coating layer.

FIG. 9 shows a design of a polymer matrix system which contains a corecontaining DMF and a polymer, a seal coating encapsulating the core, andan outer enteric coating. In this design, DMF may be released throughmatrix erosion over a sustained period of time (e.g., about 6 hours.)

FIG. 10 shows a design of an osmotic dosage form which contains anosmotic core containing DMF and a semipermeable membrane coatingencapsulating the core. The semi-permeable membrane allows water intothe tablet which creates osmotic pressure that forces the drug out ofthe coated tablet through a laser drilled hole in the coating. In thisdesign, DMF may be released over a sustained period of time (e.g., about6 hours).

FIG. 11A shows three different designs of a floating dosage formulation:a bilayer, a trilayer, and a double tablet. Each design has an activelayer, which contains DMF, and a floating layer. The bilayer designcontains only one active layer and one floating layer. The trilayerdesign contains two floating layers and one active layer in between. Thedouble tablet design has the floating layer encapsulating the activelayer. FIG. 11B shows a picture of a trilayer floating tablet, whichcontains two effervescent floating layer with one enterically coatedactive layer containing DMF, floating in simulated gastric fluid.

FIG. 12A shows a design of swellable tablet formulation for sustainedrelease. The swellable tablet contains an API (e.g., DMF) that is sealcoated and enterically coated and one or more swelling polymers. FIG.12B shows that the swellable tablet can expand significantly whichallows the swelled tablet to be retained in the stomach of a subjecttreated. FIG. 12C shows a design of swellable tablet formulation fordelayed release. The swellable tablet contains a core containing an API(e.g., DMF) that is seal coated and enterically coated and one or moreswelling polymers encapsulating the core. FIG. 12D shows another designof swellable tablet formulation for delayed release. The swellabletablet contains two layers: an active layer containing an API (e.g.,DMF) that is seal coated and enterically coated and a swelling layercontaining one or more swelling polymers. The two layers are joinedtogether to form a bilayer tablet structure.

FIG. 13A-13E shows a side view of components (FIGS. 13A-13D) in thegastroretentive folded device (FIG. 13E) of the present invention beforethe components are folded.

FIG. 14A-14E shows a side view of components (FIGS. 14A-14D) in thegastroretentive folded device (FIG. 14E) of the present invention beforethe components are folded. The DMF coated particles are incorporatedinto separate compartments (FIG. 14B) to form the integrated device.

FIGS. 15A and 15B shows a side and cross-sectional view of agastroretentive folded device of the present invention.

FIG. 16A shows the placement of a single immediate release layer on topof the outer layer of a gastroretentive folded device of the presentinvention in a cross section view. As shown in FIG. 16B, the immediaterelease layer covers the entire surface of the device.

FIG. 17A shows a drawing of the ultrasound welding on a gastroretentivefolded device of the present invention. The perimeter line of theinternal layer is shown with an arrow and the extend of welding in across section is provided in FIG. 17B.

FIG. 18 shows an exemplary welded gastroretentive folded device of thepresent invention.

FIG. 19 shows an exemplary design for a gastroretentive folded dosageform of the present invention. The dosage form has an internal layercomprising API and an outer membrane covering the internal layer. Theinternal layer and the outer membrane are then folded into an accordionconfiguration and placed into a capsule.

FIGS. 20A and 20B shows exemplary designs for gastroretentive foldeddosage form of the present invention. The dosage form shown in FIG. 20Ahas an internal layer comprising DMF coated particles of the presentinvention and two outer membranes sandwiching the internal layertherebetween. The dosage form shown in FIG. 20B has an internal layercomprising non-enterically coated DMF and two enteric layer sandwichingthe internal layer therebetween. The dosage form also has two outermember covering the two enteric layer respectively.

FIG. 21 shows the relationship between shear stress and normal stress,which is plotted to define the powder's Yield Locus.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents that can be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention.

It should be understood that any of the embodiments described herein,including those described under different aspects of the invention anddifferent parts of the specification (including embodiments describedonly in the Examples) can be combined with one or more other embodimentsof the invention, unless explicitly disclaimed or improper. Combinationof embodiments are not limited to those specific combinations claimedvia the multiple dependent claims.

Definitions

As use herein, the particle size is expressed in terms of volumediameter and the particle size distribution is expressed in terms ofD₅₀, D₁₀, D₉₀ and span.

As particles are often non-spherical, it is difficult and complex toprovide dimensional descriptions of these non-spherical particles. Asused herein, “volume diameter” refers to diameter of a sphere with equalvolume of the non-spherical particle.

In certain embodiments, the particle size described herein are measuredusing a laser diffraction technique that correlates light scattering toparticle volume on which effective length or effective diameter iscalculated. The distribution is based on a measurement of thousands ofparticles. Particle samples can be in dry form or in slurry. In oneembodiment, the instrument used to determine particle size/distributionis a Beckman Coulter LS230 or a Malvern Mastersizer.

As used herein, “D₅₀”, also known as the median diameter, corresponds tothe value under which 50% of the particles has a lower volume diameter.“D₉₀” corresponds to the value under which 90% of the particles has alower volume diameter. “D₁₀” corresponds to the value under which 10% ofthe particles has a lower volume diameter.

As used herein, “span” is a measure for particle size distribution. Itis calculated according to the following equation:

Span=(D ₉₀ −D ₁₀)/D ₅₀

In certain embodiments, powder characterization described herein can bedetermined using the FT4 Powder Rheometer (Freeman Technology Ltd,Tewkesbury, UK) with the 25 mm vessel assembly having 23.5 mm diameterblades, vented piston, a segmented rotational shear cell accessory and a10 or 25 ml borosilicate vessel. Powder testing can be generally dividedinto three categories: dynamic tests, permeability test and shear test.

Dynamic testing uses the 23.5 mm diameter blades and a 25 ml powdersample in the borosilicate test vessel. Powder is filled into the vesseland the blades are simultaneously rotated and moved axially into thepowder sample as the axial and rotational forces are measure and used tocalculate the dynamic flowability parameters, such as flow rate index(FRI) and Specific Energy (SE).

As used herein, the “flow rate index” (or FRI) is a measure of apowder's sensitivity to variable flow rate and is obtained as the ratioof the total energy required to induce powder flow at 10 mm/s and 100mm/s blade tip speed. A larger deviation from 1 indicates greatersensitivity of a powder to variable flow rate.

FRI=Flow Energy@10_(mm/s)/Flow Energy@100_(mm/s)

As used herein, “specific energy” or SE is a measure of the powder flowin low stress environment and is derived from the shear forces acting onthe blades as they rotate upward through the powder. The SE is recordedas the flow energy of the powder normalized by its weight in mJ/g duringthe upward spiral movement of the blades in a FT4 Powder Rheometerdescribe above. A lower SE is an indication of a less cohesive powderand better flow properties.

Shear testing measures powder shear properties which involves the stresslimit required to initiate a powder flow. The shear testing uses asegmented rotational shear cell head and a 10 ml powder sample in theborosilicate test vessel. Powder is filled into the vessel. The shearcell head is simultaneously rotated and moved axially under the powdersample at pre-determined normal stresses as the shear stresses aremeasured to calculate several parameters, including the flow function(FF).

As used herein, “flow function” or FF is a parameter commonly used torank powder's flowability and is determined using a shear test. The dataproduced in the shear test represents the relationship between shearstress and normal stress, which can be plotted to define the powder'sYield Locus, which is shown in FIG. 21. Fitting Mohr stress circles tothe yield locus identifies the Major Principle Stress (MPS) andUnconfined Yield Strength (UYS). Flow function is the ratio of MajorPrinciple Stress (MPS) to the Unconfined Yield Strength (UYS):

FF=MPS/UYS.

Usually, powders of low cohesion have higher FF and that representsbetter flow properties.

The permeability test measure the ease of air transmission through abulk powder which can be related to the powder's flowability. Thepermeability testing uses a vented piston with an aeration base and 10mL powder sample in the borosilicated test vessel. Powder is filled intothe vessel. The powder bed with a vested piston is exposed to varyingnormal stress increased stepwise from 1 kPa to 15 kPa. The pressure dropacross the powder bed is measure while air is flushed through the powderat a constant velocity 2 mm/s.

As used herein, “permeability” is a measure of the powder's resistanceto air flow. The permeability test utilizes the vented piston toconstrain the powder column under a range of applied normal stresses;while air is passed through the powder column. The relative differencein air pressure between the bottom and the top of the powder column is afunction of the powder's permeability. Tests can be carried out under arange of normal stresses and air flow rates. Usually, a lower pressuredrop is indicative of higher permeability and often, better flowproperties.

As used herein, “aspect ratio” is the ratio of width divided by lengthof a particle. “Elongation” is defined as 1-aspect ratio. Shapessymmetrical in all axes, such as circles or squares, will tend to havean elongation close to 0, whereas needle-shaped particles will havevalues closer to 1. Elongation is more an indication of overall formthan surface roughness.

As used herein, “convexity” is a measurement of the surface roughness ofa particle and is calculated by dividing the perimeter of an imaginaryelastic band around the particle by the true perimeter of the particle.A smooth shape, regardless of form, has a convexity of 1 while a very‘spiky’ or irregular object has a convexity closer to 0.

As used herein, “circularity” or “high sensitivity circularity” is ameasurement of the ratio of the actual perimeter of a particle to theperimeter of a circle of the same area. A perfect circle has acircularity of 1 while a very narrow rod has a High Sensitivity (HS)Circularity close to 0. The higher the HS Circularity value the closerit is to a circle. Intuitively, circularity is a measure of irregularityor the difference from a perfect circle.

As used herein, “enteric coating” refers to a coating that is stable atthe highly acidic pH (e.g., pH ˜3) found in the stomach, but breaks downrapidly at a less acidic pH (e.g., pH 7-9). In certain embodiments, thecoating does not dissolve in the stomach for at least 2 hours, 4 hours,6 hours or longer.

As used herein, “nucleation temperature” refers to the temperature forthe initial formation of a crystal from a liquid solution. Thenucleation temperature depends on the concentration of the liquidsolution.

As used herein, “a” or “an” means one or more unless otherwisespecified.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example, within 20% of the stated value. As used herein,“about” a specific value also includes the specific value, for example,about 10% includes 10%.

As used herein, the term “DMF,” “BG-12,” or “BG00012” refers to thecompound dimethyl fumarate. And the term “MMF” refers to the compound,or an ionized form of monomethyl fumarate. A compound that can bemetabolized into MMF in vivo, as used herein, includes DMF. A compoundthat can be metabolized into MMF in vivo, as used herein also includes,for example, any compound described in U.S. application Ser. No.13/760,916, the content of which is incorporated herein by reference inits entirety.

As used herein, the abbreviation API refers to MMF, a compound that canbe metabolized into MMF in vivo (e.g., DMF), or a pharmaceuticallyacceptable salt thereof or combinations thereof. In some embodiments,the API can include more than one compound, for example, a combinationof MMF and DMF. In some embodiments, the API is a single compound, e.g.,DMF. As used herein, API or DMF can also be referred to as “activeingredient” or “active agent.”

Open terms such as “include,” “including,” “contain,” “containing” andthe like mean “comprising.”

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disease or disorder.

As used herein, a controlled release dosage form may be any dosage formthat is capable of releasing a drug in a body over an extended period oftime. The controlled release dosage form herein includes, withoutlimiting to, sustained release dosage form, delayed release dosage form,and pulsatile release dosage form. In some embodiments, the controlledrelease dosage form herein is gastric retentive, which is retained inthe stomach for a period (i.e., the gastric retention time) that islonger than the normal emptying time from the stomach, e.g., longer thanabout 0.2 hours, following an average meal. In any of the embodimentsdescribed herein, the gastric retention time of a gastric retentivecontrolled release dosage form may be about 0.2 hours to about 18 hours.In some embodiments, a gastric retentive controlled release dosage formis retained in the stomach for about 0.2 hour, about 0.5 hour, about 1hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours,about 18 hours, or any ranges thereof.

The term “microtablet” means a compact in the form of a small (micro)tablet having a mean diameter of less than 5,000 microns (e.g., about1,000 microns to about 3,000 microns), excluding any coating, thatcomprises the active ingredient(s) and one or more excipients. Theactive ingredient(s) and excipients can be homogeneously orheterogeneously mixed in the microtablet. In any of the embodimentsdescribed herein, the microtablets may be coated, for example, by a sealcoating, an enteric coating, or a combination thereof.

Delivering a drug (e.g., DMF) in a pulsatile manner or in pulses may beunderstood as involving rapid and transient release of a dose of thedrug (e.g., DMF) within a short time period immediately after a lagtime.

The term “lag time” as used herein refers to the time between the timeof the beginning of delivery of a drug (e.g., DMF) from one componentand the subsequent beginning of delivery of the drug (e.g., DMF) fromanother component. For example, the lag time may refer to the timebetween the beginning of delivery of the first and second doses of anAPI upon administering a unit dosage form (e.g., as described herein).

As used herein, a pre-determined lag time of a pulsatile dosage formrefers to the lag time that may be determined by in vitro dissolutionexperiments. For example, for a pulse dosage form containing only onedose of a drug (e.g., DMF), a pre-determined lag time may refer to thetime duration between the time when the dosage form is in contact with agastric liquid or simulations thereof (i.e., the time around when animmediate release dosage form would release the drug) and the time whensubstantially all of the drug (e.g., DMF) is released from thegastro-retentive dosage form. Alternatively, for dosage forms thatcontain more than one dose of a drug (e.g., DMF), the pre-determined lagtime may refer to the time between releases of any two consecutive dosesas determined by in vitro dissolution experiments. The pre-determinedlag time herein may be from about 2 hours to about 14 hours. In someembodiments, the pre-determined lag time is about 2 hours, about 4hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours,about 14 hours, or any ranges thereof. In some embodiments, thepre-determined lag time is about 8 hours to about 12 hours. Apre-determined lag time may be controlled via various techniques. Forexample, by varying polymer components and/or thickness of lag timecontrol coatings or layers (e.g., pulsatile coatings described herein)in the controlled release dosage forms, different pre-determined lagtimes can be achieved.

The term “subject” as used herein generally refers to human, includinghealthy human or a patient with certain diseases or disorders.

As used herein, “an integrated device” is meant for any dosage formhaving a structure composed of different parts which are united togetherin one functional and physical whole, to provide, under essentially dryconditions, a structurally stable unified form. A preferred form of anintegrated device in accordance with the invention is that wherein theone or more layers are laminated so as to form a laminated device.

As used herein, “laminated” is meant for a device comprising two or morelayers/sheets (which may be the same of different), physically ofchemically attached/bound together.

As used herein, “a folded device” is meant for a device that had beenmanipulated by one or more of folding about fold lines, bending,twisting, wrapping, winding, rolling, crimping and the like. Forexample, and without being limited thereto, folding may be parallel tothe width of the unfolded device and designed to have folds which aresymmetric mirror images about a first axis. This manner of folding mayprovides an accordion-like configuration for an originally essentiallyplanar device; or the folding may be such that the folded device hasfolds of increasingly smaller amplitudes upon extending away from thefirst axis so as to form a partially rounded cross section; yet, afurther example is of a folds of increasingly larger amplitudes uponextending away from one end of the first axis to its other end, so as toform a fan-like configuration. An example of a folded device isillustrated in FIG. 4.

As used herein, “unfolded” is meant for an essentially and generallyplanar configuration of the device. The term “essentially planar” or“generally planar” denotes a fully planar as well as wiggly or wavyshape of the device. Unfolding denotes any form of expansion of thedevice, which may result form unwinding, unrolling, inflating, swelling,and the like. Following expansion in the stomach, the unfolded andessentially planar device maintains its firmness due to its uniquecharacteristics, as exemplified below

As used herein, “gastro-retentive” or “gastro-retentivity” is meant themaintenance or withholding of the agent carried by the delivery devicein the GI tract (either after being released from or still inassociation with one or more of the device's compartments/layers), for atime period longer than the time it would have been retained in thestomach when delivered in a free form or within a gastro-intestinaldelivery vehicle which is not considered gastro-retentive.Gastro-retentivity may be characterized by retention in the stomach fora period that is longer than the normal emptying time from the stomach,i.e. longer than about 2 hours, following an average meal, particularlylonger than about 3 hours and usually more than about 4, 5, 6, 7, 8, 9or 10 hours. Gastroretentivity typically means retention in the stomachfrom about 3, 4, 5, 6, 7, 8, 9 or at times 10 hours up to about 18hours. It is however noted that in accordance with the invention,retention of the gastroretentive delivery device is not observed aftermore than 48 hours after administration, and preferably not after 24hours.

As used herein “enclosing” is meant for containing, especially so as toenvelop or shelter the device in a container. The container (sometimestermed herein “envelop” or “enclosure”) may be, without being limitedthereto, a capsule (soft or solid) containing the folded device, anelongated tube, a ring or a thread (one or more) surrounding the foldeddevice, a polymeric coating (e.g. a polymeric thread wrapping the devicein a manner resembling a cocoon), a polymer or gel matrix embedding thefolded device, enclosing by molding or pressing to a form of a tabletand the like.

As used herein, “a polymer” or “polymeric composition” is meant for asingle or combination of polymers exemplified by, but not limited to,degradable polymers, non-degradable polymers, as well as a combinationof at least degradable polymer and at least one non-degradable. Apolymer may degraded in the stomach or in the intestine either throughits solubility, chemical degradation such as hydrolysis of esters orsolubilization in the gastric or the intestinal media, or throughdisintegration that is caused by the mechanical forces applied by thestomach on any solid content, or by a combination of both.

According to one embodiment, the polymer soluble in gastric contentcomprises one or more polymers selected from a hydrogel-forming polymer,a non-hydrogel polymer, or any combination thereof. Non-limitingexamples of hydrogel-forming polymer comprise proteins, polysaccharides,including gums, gelatin, chitosan, polydextrose, cellulose derivatives,such as high molecular weight grades of hydroxypropyl cellulose,hypromelose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose,methyl cellulose, polyethylene oxides, polyvinyl alcohols, solublederivatives of any one of the above as well as any combination of two ormore thereof. Non-limiting examples of non hydrogel polymer comprisepovidones (PVP), povidone, and vinyl acetate copolymers (copovidone),methacrylic acid copolymer with dimethyl amino ethyl methacrylate(Eudragit E™), low molecular weight grades of hydroxypropyl cellulose,propylene glycol alginate, polyethylene glycols, poloxamers and solublederivatives of any one of the above as well as any combination of two ormore thereof. These soluble polymers can be further cross-linked, eitherwith use of appropriate chemical cross-linking agent, or by physicalcross-linking techniques, or via exposure to gamma radiation, to controltheir mechanical properties and behavior upon contact with simulated andnatural gastric fluid.

According to another embodiment, the polymer may be a water insolublepolymer. A non-limiting list of polymers that are insoluble(non-degradable) comprises any polymer selected from a pharmaceuticallyacceptable enteric polymer, a pharmaceutically acceptable non-entericpolymer, or any combination thereof. An enteric polymer is preferablysuch that it is substantially insoluble at a pH of less than 5.5.Non-limiting examples of enteric polymers applicable with respect to theinvention include, shellac, cellacefate, hypromelose phthalate,hydroxypropyl methylcellulose acetate succinate, zein, polyvinyl acetatephthalate, aliginic acid and its salts, carboxymethyl cellulose and itssalts, methylmethacrylate-methacrylic acid copolymers, including ethylacrylate copolymers (polymethacrylates), or substantially insoluble (atpH of less than 5.5) derivatives of any one of the above as well as anyappropriate combination of two or more of the above. Non-limitingexamples of non-enteric polymers applicable with respect to theinvention include ethylcellulose; cellulose acetate; a copolymer ofacrylic acid and methacrylic acid esters, having of from about 5% toabout 10% functional quaternary ammonium groups; a polyethylene; apolyamide; a polyester; polyvinylchloride; polyvinyl acetate; and acombination of any two or more thereof.

The terms “swellable” and “swelling” mean, with respect to a polymer,that the polymer is capable of imbibing fluid and expanding when incontact with fluid present in the environment of use.

1. DMF Particles

In a first aspect, the present invention provides dimethyl fumarate(DMF) particles that have desirable bulk properties and processabilityfor drug product manufacturing.

Dimethyl fumarate (DMF) isolated from the current chemical synthesisneeds to undergo a particle size reduction process prior to drug productmanufacturing. The coarse dimethyl fumarate, with a typical meanparticle size in the range of 500-600 microns, is reduced using a jetmilling process. The reduced particles obtained by jet milling processhave shown at times poor processability during drug product manufacturedue to particle to particle cohesiveness. Larger particles, such asthose with a mean particle size of 50 microns or higher, may haveimproved flow properties. However, larger particles cannot be producedusing a jet mill with current jet milling conditions since they arealready in the lower end of equipment operating range. Further, changesto milder milling conditions (to obtain larger particles) will result invariability and oversized products. Generally, jet mill is used toreduce particles to under 20 microns.

Dimethyl fumarate also poses peculiar physical properties such assublimation, low minimum ignition energy (MIE) and sensitizing effects.As such, the handling of this compound requires careful and at timestedious procedures to avoid employee exposures and to ensure processsafety (to avoid potential dust explosion).

It is unexpectedly discovered that DMF particles having desirableparticle size, bulk properties and processability for drug productmanufacturing can be produced using a wet-milling process. Thewet-milling process reduces the exposure of DMF dust to employee,providing a safer process.

In one embodiment, the DMF particles of the present invention have amedian diameter (D₅₀) between 40 μm and 150 μm. In certain embodiments,the D₅₀ value for the DMF particles of the present invention is between50 μm and 130 μm, between 60 μm and 130 μm, between 70 μm and 130 μm,between 50 μm and 100 μm, between 60 μm and 100 μm, between 70 μm and100 μm, between 80 μm and 100 μm or between 80 μm and 90 μm.

In one embodiment, the DMF particles of the present invention areuniformly distributed. In certain embodiments, the DMF particles of thepresent invention have a span that is less than 2.0 (e.g., less than1.9, less than 1.8, less than 1.7, or less than 1.6). In one embodiment,the span for the DMF particles of the present invention is in the rangeof 1.3 to 1.9, 1.4 to 1.9, or 1.5 to 1.9. In another embodiment, thespan is in the range of 1.5 to 1.8. In another embodiment, the span isin the range of 1.3 to 1.7 or 1.3 to 1.8. In yet another embodiment, thespan is in the range of 1.3 to 1.5.

In certain embodiments, less than 10% (e.g., less than 9%, less than 8%,less than 7%, less than 6%, etc.) of the DMF particles has a particlesize below 10 μm. In another embodiment, less than 5% (e.g., less than4%, less than 3%, less than 2% or less than 1%) of the DMF particles hasa particle size below 5 μm.

In certain embodiment, the DMF particles of the present invention havedesirable solid properties suitable for manufacturing process. The DMFparticles of the present invention have one or more properties asdescribed below.

In some embodiments, the DMF particles of the present invention have aflow rate index (FRI) that is less than 1.7 (e.g., less than 1.5, lessthan 1.4, or less than 1.3). In another embodiment, the FRI for the DMFparticles of the present invention is less than 1.25, less than 1.20,less than 1.15 or less than 1.10. In one embodiment, the FRI for the DMFparticles of the present invention is in the range of 1.0 to 1.7, 1.1 to1.7, 1.0 to 1.6, 1.0 to 1.5, 1.0 to 1.4, 1.0 to 1.3 or 1.0 to 1.25. Inanother embodiment, the FRI is the in the range of 1.3 to 1.7.

In some embodiments, the DMF particles of the present invention have aspecific energy (SE) that is less than 15.0 (e.g., less than 14.0, lessthan 13.0, less than 12.0, less than 11.0, less than 10.0, less than9.0, less than 8.0, less than 7.0, less than 6.0 or less than 5.0). Inone embodiment, SE for the DMF particles of the present invention is inthe range of 4.0 to 15.0, 4.0 to 14.0, 4.0 to 13.0, 4.0 to 12.0, 4.0 to11.0, 4.0 to 10.0, 4.0 to 9.0, 4.0 to 8.0, 4.0 to 7.0, 4.0 to 6.8, 4.0to 6.5, 4.0 to 6.0 or 4.0 to 5.0. In another embodiment, the SE is inthe range of 6.0 to 13.0, 6.0 to 13.0 or 10.0 to 13.0.

In some embodiments, the DMF particles of the present invention have aflow function (FF) that is greater than 2.0 (e.g., greater than 3.0,greater than 4.0, greater than 5.0, greater than 6.0, greater than 7.0,greater than 8.0, greater than 9.0 or greater than 10.0). In oneembodiment, the flow function for the DMF particles of the presentinvention is in the range of 2.0 to 20.0, 2.0 to 15.0, 2.0 to 11.0, 2.5to 15.0, 2.5 to 10.0, 4.0 to 20.0, 8.0 to 20.0, 2.5 to 8.0, 2.5 to 6.0,4.0 to 10.0, 4.0 to 11.0, or 8.0 to 15.0.

In some embodiments, when subjected to a permeability test at 1 kPausing a FT4 powder rheometer, the pressure drop for the DMF particles ofthe present invention is less than 0.4 mbar (e.g., less than 0.35 mbar,less than 0.30 mbar, less than 0.25 mbar, less than 0.20 mbar, less than0.15 mbar or less than 0.10 mbar).

In some embodiments, when subjected to a permeability test at 15 kPausing a FT4 powder rheometer, the pressure drop for the DMF particles ofthe present invention is less than 0.5 mbar (e.g., less than 0.4 mbar,less than 0.35 mbar, less than 0.3 mbar, less than 0.25 mbar, less than0.20 mbar, less than 0.15 mbar, or less than 0.1 mbar).

In a 1^(st) specific embodiment, the DMF particles of the presentinvention have a D₅₀ value in the range of 50 μm to 100 μm and a span inthe range of 1.3 to 1.9.

In a 2^(nd) specific embodiment, the DMF particles of the presentinvention have a D₅₀ value in the range of 80 μm to 100 μm and a span inthe range of 1.3 to 1.7.

In a 3^(rd) specific embodiment, the DMF particles of the presentinvention (e.g., the DMF particles described in the 1^(st) or 2^(nd)specific embodiments have the following powder properties:

(i) FRI in the range of 1.0 to 1.7;

(ii) SE in the range of 4.0 to 13.0;

(iii) FF in the range of 2.0 to 11.0;

(iv) pressure drop less than 0.35 mbar when subjected to a permeabilitytest at 1 kPa;

(v) pressure drop less than 0.35 mbar when subjected to a permeabilitytest at 15 kPa.

In a 4^(th) specific embodiment, the DMF particles of the presentinvention (e.g., the DMF particles described in the 1^(st) or 2^(nd)specific embodiment) have the following powder properties:

(i) FRI in the range of 1.0 to 1.4; and

(ii) FF in the range of 5.0 to 15.0.

In a 5^(th) specific embodiment, the DMF particles of the presentinvention (e.g., the DMF particles described in the 1^(st), 2^(nd),3^(rd) or 4^(th) specific embodiment) have the following powderproperties:

(i) pressure drop less than 0.3 mbar when subjected to a permeabilitytest at 1 kPa; and

(ii) pressure drop less than 0.3 mbar when subjected to a permeabilitytest at 15 kPa.

In 6^(th) specific embodiment, the DMF particles of the presentinvention (e.g., the DMF particles described in the 1^(st), 2^(nd),3^(rd), 4^(th) or 5^(th) specific embodiment) have a SE in the range of4.0 to 7.0.

In a 7^(th) specific embodiments, the DMF particles of the presentinvention (e.g., the DMF particles described in the 1^(st), 2^(nd),3^(rd), 4^(th), 5^(th) or 6^(th) specific embodiment) have a threedimensional morphology.

In one embodiment, the DMF particles of the present invention havehigher percentage of thicker particles as compared to the DMF particlesprepared by jet-milling process. The percentage of thicker particles canbe determined using Malvern Instrument Morphologi G3. Morphologi G3measures the size and shape of particles by the technique of staticimage analysis. The intensity of light is quantified by the grey scalefactor which depends on the amount of light reaching the detector. Thegrey scale image of a particle ranges from 0 (black) to 255 (white) andit is related to the thickness of the particle. The lower the intensityvalue the darker the image therefore the thicker the particle. Incertain embodiments, the DMF particles of the present invention havegreater than 30%, greater than 40%, greater than 45% or greater than 50%of the particles with intensity less than 80. In one embodiment,30-100%, 30-90%, 30-80%, 30%-70%, 30-60%, 40-60% or 40-50% of the DMFparticles of the present invention have intensity less than 80.

In another embodiment, the DMF particles are slightly less elongated,more circular and less edgy, as indicated by higher aspect ratio, higherHS circularity and higher convexity values, respectively, than the DMFparticles prepared by the jet-milling process.

In one embodiment, the DMF particles of the present invention has acircularity value in the rang of 0.8 to 0.95. In another embodiment, 40%of the DMF particles by accumulated volume has a circularity value inthe range of 0.8 to 0.9.

In another embodiment, the DMF particles of the present invention has anaspect ratio in the range of 0.55 to 1.0.

In yet another embodiment, the DMF particles of the present inventionhas a convexity value in the range 0.95 to 1.0.

The three dimensional morphology renders the DMF particles of thepresent invention more suitable for drug product manufacturing, e.g.,coating, mixing, compression, extrusion etc., than DMF particlesprepared by the jet-milling process.

The DMF particles of the present invention can be prepared by anysuitable processes known in the art. In certain embodiments, the DMFparticles of the present invention are prepared by a process describedherein.

In one aspect, the present invention provides new processes forpreparing the DMF particles of the present invention.

In one embodiment, the process comprises the step of reducing DMFparticle size by wet-milling. Wet-milling processes known in the art canbe used in the processes of the present invention. According to thepresent invention, wet-milling can be performed using any kind of mill,e.g., disc mills, colloid mills or other shear mixer. In one embodiment,wet-milling in the processes of the present invention is performed usinga high-shear mixer, e.g., an inline high-shear mixer (e.g., SilversonVerso inline mixer or IKA MagicLab inline mixer).

One process of the present invention comprises the step of wet-milling aslurry of DMF particles until desired particle size reduction isachieved.

In a first process, the slurry of DMF can be generated by cooling asolution of DMF to below its nucleation temperature. The solution of DMFcan be original reaction mixture of fumaric acid and methanol uponcompletion of the reaction. The reaction can be carried out in anysuitable solvent or any combination of solvents. In one embodiment,methanol is used as solvent. Alternatively, the solution of DMF can beprepared by dissolving coarse DMF in suitable solvent, such as methanol.Generally, the solvent is heated until complete dissolution of coarseDMF. In another alternative, the solution of DMF can be recycled motherliquor from previous wet-milling process.

In certain embodiments, the solution of DMF is a methanol solution andis 80%, 85%, 90%, 95% or 99.9% saturated at the boiling temperature ofmethanol, i.e., 64°—65°.

In one embodiment, the solution of DMF (e.g., direct reaction mixture inmethanol) is cooled to temperature in the range of 60° C.-62° C. togenerate a slurry comprising precipitated DMF before starting thewet-milling step.

In one embodiment, the slurry is continuously cooled during thewet-milling step. Generally, the slurry is cooled to a certaintemperature to maximize precipitation of DMF. In one embodiment, theslurry is cooled to a temperature in the range of 10°—25° C. Morespecifically, the slurry is cooled to a temperature in the range of10°—15° C. Generally, the solution is cooled down slowly. In certainembodiments, the slurry is cooled over a period of 4 to 20 hours, 4 to15 hours, 4 to 10 hours, or 4 to 8 hours.

Alternatively, in a second process, a slurry comprising DMF is subjectedto wet-milling until desired particle size reduction is achieved. Theslurry of DMF can by formed by cooling a saturated DMF solution.Alternatively, DMF can be combined with a suitable solvent to provide aslurry comprising DMF. In one embodiment, the solvent is methanol. Inanother embodiment, DMF in the slurry is DMF crystals.

In a third process, a slurry of DMF is provided at a temperature between50° C. to below its nucleation temperature. The slurry is then subjectedto wet-milling until desired particle size reduction is achieved.Accordingly, in one embodiment, the process of the present inventioncomprises the steps of:

a) providing a slurry of DMF at a temperature in the range of 50° C. tobelow its nucleation temperature; and

b) wet-milling the slurry until desired particle size reduction isachieved.

The slurry can be prepared by combining DMF with a suitable solvent andheating the solvent-DMF mixture to a temperature below its dissolutiontemperature or nucleation temperature. In one embodiment, thetemperature is in the range of 50° C. to below nucleation temperature.In another embodiment, the slurry of DMF is at a temperature in therange of 60° C.—62° C.

In one embodiment, the wet-milling in step b) is carried out while theslurry is continuously cooled. The slurry is cooled to a certaintemperature to maximize precipitation of DMF. In one embodiment, theslurry is cooled to a temperature in the range of 10°—25° C. Morespecifically, the slurry is cooled to a temperature in the range of10°—15° C. Generally, the solution is cooled down slowly. In certainembodiments, the slurry is cooled over a period of 4 to 20 hours, 4 to15 hours, 4 to 10 hours, or 4 to 8 hours.

In certain embodiments, the wet-milling in the processes described aboveis carried out by recirculating the slurry comprising DMF through ahigh-shear mixer until the desired particle size reduction is reached.The DMF particle size can be monitored during the wet-milling step.

In certain embodiments, for the processes described above (e.g., thefirst, second or third process), the process further comprises heatingthe slurry comprising DMF after the wet-milling step to a temperaturebelow its nucleation temperature followed by cooling the heated slurry.In one embodiment, the slurry is heated to a temperature in the range of20-50° C. More specifically, the slurry is heated to a temperature inthe range of 38-42° C. Alternatively, the slurry is heated to about28-32° C. In certain embodiments, for the process described above, theslurry is heated at 1° C./minute rate.

In some embodiments, for the process described above, the heated slurryis cooled to a temperature in the range of 0°—15° C., 0°—10° C. or 0°—5°C. In one embodiment, the slurry is cooled at 1° C./minute rate.

In some embodiments, any one of the processes described above furthercomprises isolating the DMF particles after the wet-milling step.

2. DMF Coated Particles

In a second aspect, the present invention provides dimethyl fumarate(DMF) coated particles, wherein the coated particles comprising DMFstarting particles coated with an enteric coating. As used herein, DMFstarting particles refer to DMF particles before they are coated with anenteric coating. The DMF coated particles of the present invention arehighly stable in gastric fluid, suitable for use in gastro-retentiveformulations or dosage forms. In addition, the DMF coated particles havesmaller particle size than enterically coated DMF particles known in theart, which makes them suitable to be used in certain gastro-retentivedosage forms described below.

In a 1^(st) specific embodiment, the DMF coated particles of the presentinvention releases no more than 25%, or no more than 20% of the API(e.g., DMF) over 4 to 12 hours when subjected to an in vitro dissolutiontest employing USP Simulated Gastric Fluid (SGF) without pepsin asdissolution medium. In one embodiment, no more than 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6% or 5% of DMF is releasedfrom the DMF coated particles over 4 to 12 hours.

In a 2^(nd) specific embodiment, the DMF coated particles of the presentinvention (e.g., the DMF coated particles descried in the 1^(st)specific embodiment) have a particle size less than 500 μm, less than400 μm, or less than 300 μm. In one embodiment, the DMF coated particleshave a particle size in the range of 100 μm to 500 μm, 100 μm to 400 μm,100 μm to 350 μm, or 130 μm to 350 μm. In another embodiment, the DMFcoated particles have a median diameter (D₅₀) in the range of 100 μm to500 μm, 100 μm to 400 μm, 150 μm to 300 μm, 100 μm to 250 μm, 150 μm to250 μm, or 150 μm to 200 μm.

In a 3^(rd) specific embodiment, the DMF coated particles of the presentinvention (e.g., the DMF coated particles descried in the 1^(st) or2^(nd) specific embodiment) are uniformly distributed in size. In oneembodiment, the DMF coated particles have a span that is equal to orless than 1.5 (e.g., less than 1.4, less than 1.3, less than 1.2, lessthan 1.0, less than 0.9, less than 0.8, less than 0.7, less than 0.6, orless than 0.5). In one embodiment, the span for the DMF coated particlesof the present invention is in the range of 0.5 to 1.5, 0.5 to 1.2, 0.5to 1.0, 0.5 to 0.9, 0.5 to 0.8 or 0.6 to 0.8.

In a 4^(th) specific embodiment, in the DMF coated particles of thepresent invention (e.g., the DMF coated particles descried in the1^(st), 2^(nd) or 3^(rd) specific embodiment), the weight of the entericcoating is greater than 30% of the weight of the DMF starting particles,i.e., greater than 30% weight gain. In one embodiment, the weight of theenteric coating is greater than 40%, 50%, 60%, 70%, 80%, 90%, 110% or120% of the weight of the DMF starting particles. In one embodiment, theweight of the enteric coating is 30-200%, 50-150%, 60-150%, 70-150%,80-150%, 80-120% or 90-120% of the DMF starting particles.

Any enteric coating materials known in the art can generally be used inthe present invention. In certain embodiments, the enteric coatingcomprises an excipient selected from the group consisting of a copolymerof methacrylic acid and methyl methacrylate, a copolymer of methacrylicacid and ethyl acrylate, hypromellose phthalate (HPMCP), celluloseacetate phthalate. More specifically, the enteric coating comprises acopolymer of methacrylic acid and methyl methacrylate. Even morespecifically, the ratio of methacrylic acid to methyl methacrylate inthe copolymer is 0.8:1 to 1.2:1, (e.g., 1:1). In an even more specificembodiment, the enteric coating comprises EUDRAGIT® L 100(poly(methacylic acid-co-methyl methacrylate) 1:1).

In certain embodiments, the enteric coating of the present inventionfurther comprises one or more plasticizers. Exemplary plasticizersinclude, but are not limited to, acetyltriethyl citrate, benzylbenzoate, castor oil, chlorobutanol, diacetylated monoglycerides,dibutyl sebacate, diethyl phthalate, glycerin, mannitol, polyethyleneglycol, polyethylene glycol monomethyl ether, propylene glycol,pullulan, sorbitol, sorbitol sorbitan solution, triacetin, tributylcitrate, triethyl citrate and Vitamin E. In a more specific embodiment,the plasticizer is triethyl citrate.

In one embodiment, the enteric coating of the present inventioncomprises EUDRAGIT® L 100 and triethyl citrate. More specifically, theweight ratio of the triethyl citrate to EUDRAGIT® 100 is from 1:1 to1:20, from 1:1 to 1:10 or from 1:3 to 1:8. Even more specifically, theweight ratio of the triethyl citrate to EUDRAGIT® L 100 is 1:5.

In a 5^(th) specific embodiment, the DMF coated particles of the presentinvention:

(i) releases no more than 15% of the API (e.g., DMF) over 4 to 12 hourswhen subjected to an in vitro dissolution test employing USP SimulatedGastric Fluid (SGF) without pepsin as dissolution medium;

(ii) have a median diameter (D₅₀) in the range of 100 μm to 250 μm witha span in the range of 0.5 to 1.0; and

(iii) comprise an enteric coating, wherein the weight of the entericcoating is 80-120% of the weight of the DMF starting particles.

In a 6^(th) specific embodiment, for the DMF coated particles describedin the 5^(th) specific embodiment above, the enteric coating comprises acopolymer of methacrylic acid and methyl methacrylate (e.g., EUDRAGIT® L100 (poly(methacylic acid-co-methyl methacrylate) 1:1). In a morespecific embodiment, the enteric coating further comprises aplasticizer. Even more specifically, the plasticizer is triethylcitrate. In another more specific embodiment, the enteric coatingcomprises EUDRAGIT® L 100 and triethyl citrate, wherein the weigh ratioof the triethyl citrate to EUDRAGIT® L 100 is 1:5.

In certain embodiments, the DMF starting particles in the DMF coatedparticles of the present invention (e.g., DMF coated particles describedin the second aspect of the invention or the 1^(st), 2^(nd), 3^(rd), 4^(th), 5^(th) or 6^(th) specific embodiment or any more specificembodiments described therein) are the DMF particles described in thefirst aspect of the invention (e.g. the DMF particles described in the1^(st), 2^(nd), 3^(rd), 4^(th), 5^(th), 6^(th) or 7^(th) specificembodiment or any more specific embodiments described therein).

3. Dosage Forms

The present invention provides dosage forms comprising DMF coatedparticles described in the second aspect of invention or any specificembodiments described therein.

In certain embodiments, the dosage forms (e.g. unit dosage form) of thepresent invention are suitable for once a day dosing. The dosage forms(e.g. unit dosage form) of the present invention are also believe tohave improved DMF absorption.

A. Controlled Release Dosage Form

In a third aspect, the present invention provides controlled releasedosage forms comprising the DMF coated particles described above in thesecond aspect of invention or any embodiments described therein.

In various embodiments, the invention provides a controlled releasedosage form that releases MMF, a compound that can be metabolized intoMMF in vivo (e.g., DMF), or a pharmaceutically acceptable salt thereofor combinations thereof (collectively “API”), in the gastrointestinal(“GI”) tract of a subject in a sustained or pulsatile manner. In someembodiments, the API in the controlled release dosage form is retainedin the stomach and/or small intestine of a subject treated for at least3 hours (e.g., about 3 hours, about 4 hours, about 5 hours, about 6hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, or any ranges thereof). In someembodiments, the API in the controlled release dosage form is retainedin the stomach and/or small intestine for about 3 hours to about 17hours. In some embodiments, the API in the controlled release dosageform is retained in the stomach and/or small intestine of a subjecttreated for at least 4 hours, at least 5 hours, at least 6 hours, atleast 7 hours, or at least 8 hours. In some embodiments, the API in thecontrolled release dosage form is retained in the stomach and/or smallintestine of a subject treated for at least 5 hours, at least 6 hours,or at least 7 hours.

The controlled release dosage form can be a matrix dosage form, anosmotic dosage form, a gastric retention dosage form, an intestinalretention dosage form, or a combination thereof.

In some embodiments, a daily amount of the API (e.g., 480 mg of DMF) isprovided by one or more units of the controlled release dosage systemalone. In some embodiments, the daily amount of the API is provided byone or more units of the controlled release dosage form in combinationwith one or more units of an enterically coated immediate release dosageform.

In some embodiments, a subject administered one or more units (e.g., 1,2, 3, 4, 5, or 6) of the controlled release dosage form (with or withoutfood) once daily produces one or more of the following pharmacokineticparameters in the subject: (a) a mean plasma MMF AUC_(overall) rangingfrom about 4.81 h·mg/L to about 11.2 h·mg/L; (b) a mean plasma MMFAUC₀₋₁₂ ranging from about 2.4 h·mg/L to about 5.5 h·mg/L; and (c) amean AUC_(0-infinity) ranging from about 2.4 h·mg/L to about 5.6 h·mg/L.In some embodiments, the subject treated exhibits a pharmacokineticprofile characterized by both (a) and (b), both (a) and (c), or both (b)and (c). In some embodiments, the subject treated exhibits apharmacokinetic profile characterized by (a), (b), and (c).

In some embodiments, a subject administered a single unit of thecontrolled release dosage form (with or without food) or a unit dosageform described herein once daily produces one or more of the followingpharmacokinetic parameters in the subject: (a) a mean plasma MMFAUC_(overall) ranging from about 4.81 h·mg/L to about 11.2 h·mg/L; (b) amean plasma MMF AUC₀₋₁₂ ranging from about 2.4 h·mg/L to about 5.5h·mg/L; and (c) a mean AUC_(0-infinity) ranging from about 2.4 h·mg/L toabout 5.6 h·mg/L. In some embodiments, the subject treated exhibits apharmacokinetic profile characterized by both (a) and (b), both (a) and(c), or both (b) and (c). In some embodiments, the subject treatedexhibits a pharmacokinetic profile characterized by (a), (b), and (c).

In some embodiments, a subject orally administered a single unit of thecontrolled release dosage form or a unit dosage form described herein(with or without food) once daily exhibits a mean MMF plasma area underthe curve 0-12 (AUC₀₋₁₂) of about 2.36 h·mg/L to about 5.50 h·mg/L, fromabout 2.75 h·mg/L to about 5.10 h·mg/L, or from about 3.14 h·mg/L toabout 4.91 h·mg/L. In one embodiment, the subject exhibits a meanAUC₀₋₁₂ of about 3.93 h·mg/L.

In some embodiments, a subject orally administered a single unit of thecontrolled release dosage form or a unit dosage form described herein(with or without food) once daily exhibits a mean MMF plasma overallarea under the curve (AUC_(overall)) of about 4.81 h·mg/mL to about 11.2h·mg/mL, or from about 6.40 h·mg/L to about 10.1 h·mg/L. In oneembodiment, the subject exhibits a mean AUC_(overall) of about 8.02h·mg/L.

In some embodiments, suitable amounts of API for the controlled releasedosage form include those that can provide, by itself or in combinationwith one or more doses from, for example, a second dosage form (e.g., acontrolled release dosage form or an enterically coated immediaterelease dosage form), a daily amount of the respective compound (e.g.,DMF) ranging from about 1 mg/kg to about 50 mg/kg (e.g., from about 2.5mg/kg to about 20 mg/kg or from about 2.5 mg/kg to about 15 mg/kg).

The controlled release dosage form contains any therapeuticallyeffective dose of an API, e.g., an amount that is effective in treatingmultiple sclerosis. For example, suitable doses of DMF in the controlledrelease dosage form may be any dose from about 20 mg to about 1 g ofDMF. In some embodiments, the suitable doses of DMF in the controlledrelease dosage form may be any dose from about 80 mg to about 1000 mg ofDMF. In some embodiments, the suitable doses of DMF in the controlledrelease dosage form may be any dose from about 100 mg to about 750 mg ofDMF. In some embodiments, the suitable doses of DMF in the controlledrelease dosage form is about 200 to about 600 mg. In some embodiments,the suitable doses of DMF in the controlled release dosage form may beany dose from about 300 to about 600 mg. In some embodiments, thesuitable doses of DMF in the controlled release dosage form is about 480mg.

In some embodiments, the DMF in the controlled release dosage form isabout 60 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg,about 200 mg, about 240 mg, about 320 mg, about 360 mg, about 400 mg,about 480 mg, about 600 mg, about 720 mg, about 800 mg, about 900 mg,about 1000 mg of DMF, or any ranges thereof.

The controlled release dosage form can contain an amount of a compoundthat that can metabolize into MMF that provides an equivalent amount ofMMF as the doses of DMF described above.

In some embodiments, the daily amount of the API is provided by one ormore units (e.g., 1, 2, 3, 4, or 5) of the controlled release dosageform herein. In some embodiments, the daily amount of the API isprovided by a single unit of the controlled release dosage form herein,i.e., one unit per day. In some embodiments, one or more units (e.g., 1,2, 3, 4, or 5) of the controlled release dosage form herein isco-administered with one or more units (e.g., 1, 2, 3, 4, or 5) of asecond dosage form (e.g., as described herein) to provide the dailyamount of the API to a subject. In some embodiments, the daily amount ofthe API is provided by one or more units (e.g., 1, 2, 3, 4, or 5) of thecontrolled release dosage form described herein and one or more units(e.g., 1, 2, 3, 4, or 5) of an enterically coated immediate releasedosage form (e.g., as described herein). For example, in someembodiments, two units of the controlled release dosage form (e.g., twoof the osmotic dosage form described herein) and one enterically coatedimmediate release dosage form is combined, for example, in a capsule, ora tablet, to provide the daily amount of the API (e.g., DMF) to asubject.

In some embodiments, the controlled release dosage form comprises anacid soluble outer coating. Suitable acid soluble coatings for the firstdosage component are known in the art and include those coatings thatdissolve at a pH less than 6.0. Non-limiting examples of acid solublecoatings include gelatin, Eudragit® E-100, polyvinyl acetyldiethylaminoacetate, and chitosan coatings. The acid-soluble coating maybe applied using various techniques (e.g., spray techniques) known toone skilled in the art.

In addition to the components listed below for each controlled releasedosage form, the controlled release dosage form may also comprise one ormore pharmaceutically acceptable excipients in addition to thosedescribed above. Suitable pharmaceutically acceptable excipients arethose known in the art, for example, binders, fillers, disintegrants,glidants, lubricants, diluents, plasticizers, etc. as described inRemington's Pharmaceutical Science, 18^(th) Edition, 1990, MackPublishing Company, Easton, Pa. (“Remington's”).

a. Matrix Dosage Form

In some embodiments, the invention provides a matrix dosage form fordelivering an API to a subject treated. The matrix dosage form hereincomprises a core comprising an API (e.g., DMF coated particles describedabove in the second aspect or any embodiments described therein), one ormore release modifying polymers, and one or more pharmaceuticallyacceptable excipients. Suitable release modifying polymers for a matrixdosage form include cellulose and cellulose derivatives, such asmicrocrystalline cellulose, hydroxypropyl methyl cellulose,hydroxypropyl cellulose and methylcellulose, Eudragit polymers (e.g.,Eudragit RS, RL), povidone, polyvinyl acetate, poly(ethyleneoxide)(PEO), polyethylene glycol (PEG), poly (vinyl alcohol) (PVA), xanthangum, carrageenan and other synthetic materials. The amount of therelease modifying polymers can be from about 2% to about 50% by weightof the matrix dosage form. In some embodiments, the amount of therelease modifying polymers can be about 2%, about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, or any ranges thereof, by weight of the matrix dosage form.Various techniques for preparing a matrix dosage form are known.

The matrix dosage form herein may also be coated. In some embodiments,the matrix dosage form comprises a seal coating encapsulating the core.In some embodiments, the matrix dosage form comprises an outer entericcoating. In some embodiments, the outer enteric coating encapsulates aseal coating. Various techniques for coating are known.

In some embodiments, the matrix dosage form exhibits zero-order releaseof the API. In some embodiments, the matrix dosage form releases the APIin the GI tract of a subject in a sustained period of time from about 2to about 24 hours (e.g., about 2, about 4, about 6, about 8, about 10,about 12, about 14, about 16, about 18, about 20, about 22, about 24hours, or any ranges thereof). In some embodiments, the matrix dosageform releases the API in the GI tract of a subject in about 2 to about10 hours. In some embodiments, the matrix dosage form releases the APIin the GI tract of a subject in about 4 to about 6 hours. In someembodiments, the API is released in the stomach. In some embodiments,the API is released in the upper GI tract. In some embodiments, the APIis released in the lower GI tract. In some embodiments, the API isreleased in the small intestine.

The rate of release can be modified by varying the amount, type, andratio of the one or more release modifying polymers.

The rate of release can also depend on the form (e.g., tablet ormicrotablets) of the matrix dosage form. In some embodiments, the matrixdosage form comprising the API is a bilayer or monolithic tablet. Insome embodiments, the matrix dosage form comprises a plurality ofmicrotablets comprising the API. In some embodiments, the bilayer ormonolithic tablet, or the microtablets are coated (e.g., entericallycoated).

The release profile of the matrix dosage form herein can be determinedby an in vitro dissolution method. Standard test protocols for in vitrodissolution are known. In some embodiments, the release profile of thematrix dosage form is characterized in that more than about 80% of theAPI is released in less than about 8 hours (e.g., about 6 hours, about 4hours), when tested by United State Pharmacopoeia (USP) DissolutionApparatus 2 according to standardized and specified in USP GeneralChapter <711> Dissolution, at an agitation speed of 75 rpm. In someembodiments, the release profile of the matrix dosage form ischaracterized in that more than about 80% of the API is released in lessthan about 8 hours (e.g., about 6 hours, about 4 hours), when tested byUnited State Pharmacopoeia (USP) Dissolution Apparatus 2 according tostandardized and specified in USP General Chapter <711> Dissolution, atan agitation speed of 100 rpm.

b. Osmotic Dosage Form

In any of the embodiments described herein, the controlled releasedosage form is an osmotic dosage form. Various techniques for preparingan osmotic dosage form that include, but are not limited to monolithictablets, bilayer tablets, and trilayer tablets, are known. In someaspects, the osmotic dosage form comprises an osmotic monolithic tablet.

An osmotic dosage form can be a tablet with a semi-permeable membrane.The semi-permeable membrane allows water into the tablet which dissolvesan osmotic agent that creates osmotic pressure and/or a hydrophilicpolymer that suspends and carries the drug out of the coated tabletthrough a laser drilled hole in the coating.

The osmotic dosage form herein can include an osmotic core comprising anAPI (e.g., DMF coated particles described above in the second aspect orany embodiments described therein), one or more osmotic agents, one ormore pharmaceutically acceptable excipients, and optionally one or morerelease modifying polymers. In some embodiments, the semi-permeablemembrane coated tablets could be encapsulated in a gelatin capsule.Suitable material for the semi-permeable membrane coatings includesthose known in the art, for example, cellulose products such ascellulose acetate, ethyl cellulose, hydroxyalkyl cellulose (e.g.,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose). Suitable osmotic agents include those known in the art, forexample, a sugar such as sorbitol, mannitol, xylitol, fructose or salts(e.g. sodium chloride). In some embodiments, the osmotic agents can bein an amount of about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, or any ranges thereof, by weight of total weight of theosmotic dosage form. In some embodiments, the semi-permeable membranecoatings can be in an amount of about 2% to about 20% (e.g., about 2%,about 5%, about 10%, about 15%, about 20%, or any ranges thereof) byweight of total weight of the osmotic dosage form.

Other suitable material for the osmotic dosage form include those knownin the art, for example, the osmotic dosage form may comprise a waterswellable polymer (e.g. polyethylene oxide), a water soluble polymer, awater insoluble polymer (e.g. sodium carboxyl methyl cellulose), a waterinsoluble and water swellable polymer, a water insoluble and waterpermeable polymer, or combinations thereof.

In some embodiments, the osmotic dosage form comprises a polymerselected from the group consisting of homopolymer of N-vinylpyrrolidone, copolymer of N-vinyl pyrrolidone, copolymer of N-vinylpyrrolidone and vinyl acetate, copolymer of N-vinyl pyrrolidone andvinyl propionate, methylcellulose, ethylcellulose,hydroxyalkylcelluloses, hydroxypropylcellulose,hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulosephthalate, cellulose succinate, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulosesuccinate, hydroxypropylmethylcellulose acetate succinate, polyethyleneoxide, polypropylene oxide, copolymer of ethylene oxide and propyleneoxide, methacrylic acid/ethyl acrylate copolymer, methacrylicacid/methyl methacrylate copolymer, butylmethacrylate/2-dimethylaminoethyl methacrylate copolymer,poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymerof vinyl acetate and crotonic acid, partially hydrolyzed polyvinylacetate, carrageenan, galactomannan or xanthan gum polyethylene oxide,and hydroxypropyl methylcellulose.

In some embodiments, the osmotic dosage form comprises a polymerselected from the group consisting of hydroxypropylcellulose,cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose,pregelatinized starch, sodium starch glycolate, polyvinyl acetate,polyacrylic acid, acrylate-co-polymer, carboxymethylcellulose calcium,carboxymethylcellulose sodium, poly(hydroxyethyl-methacrylate),poly(methacrylic acid), poly(acrylamide), sodium starch glycolate,starch, poly(hydroxyalkyl methacrylate) with a molecular weight of32,000 to 5,500,000, poly(electrolyte) complexes, poly(vinyl alcohol),acrylate polymers with water absorbability of roughly 400 times itsoriginal weight, a mixture of poly(vinyl alcohol) andpoly(N-vinyl-2-pyrrolidone), poly(acrylic acid) with a molecular weightof 80,000 to 200,000, polyoxy polyethylene oxide polymers with amolecular weight of 100,000 to 5,000,000, polysaccharides, agar, acacia,karaya, tragacanth and algins, pectin with a molecular weight of 30,000to 300,000, and polyoxybutylenepolyethylene block polymer.

In some embodiments, the osmotic dosage form comprises a polymerselected from the group consisting of cellulose acylate, celluloseacetate, cellulose diacylate, cellulose diacetate, cellulose triacylate,cellulose triacetate, mono-, di-, and tri-cellulose alkanylate, mono-,di- and tri-alkenylates, mono-, di- and tri-aroylates, cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrioctanoate, cellulose tripropionate, cellulose diesters, cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedicarpylate, cellulose actate heptonate, cellulose valerate palmitate,cellulose acetate octonoate, cellulose propionate succinate, celluloseacetate valerate, cellulose acetaldehyde, dimethyl cellulose acetate,cellulose acetate ethylcarbamate, hydroxypropylmethylcellulose,semipermeable polyamylsulfanes, semipermeable urethane, celluloseacetate methylcarbamate, cellulose dimethylaminoacetate, semipermeablesulfonated polystyrenes, semipermeable silicone rubbers, semipermeablestyrenes, sulfonated polystyrenes, polyurethanes,polydiethylaminomethylstyrene, cellulose acetate methylcarbamate,ethylcellulose, shellac, polymethylstyrene, polyvinylacetate,seimpermeble (polysodium styrenesulfonate), and semipermeablepoly(vinylbenzymtrimethylammonium chloride.

In some embodiments, the osmotic dosage form comprises a polyethyleneoxide or hydroxypropyl methylcellulose. Various commercially availablepolyethylene oxide (e.g., Polyox N-80, WSR N-750 or WSR-205) andhydroxypropyl methylcellulose (e.g., Methocel K 100 Premium LV or E50Premium LV) are suitable for use in the osmotic dosage form.

In some embodiments, the osmotic dosage form releases the API andexhibits zero-order release of the API. In some embodiments, the osmoticdosage form releases the API in the GI tract of a subject in a sustainedperiod of time from about 2 to about 24 hours (e.g., about 2, about 4,about 6, about 8, about 10, about 12, about 14, about 16, about 18,about 20, about 22, about 24 hours, or any ranges thereof). In someembodiments, the osmotic dosage form releases the API in the GI tract ofa subject in about 2 to about 10 hours. In some embodiments, the osmoticdosage form releases the API in the GI tract of a subject in about 4 toabout 6 hours. In some embodiments, the API is released in the stomach.In some embodiments, the API is released in the upper GI tract. In someembodiments, the API is released in the lower GI tract. In someembodiments, the API is released in the small intestine.

The release profile of the osmotic dosage form herein can also bedetermined by an in vitro dissolution method. Standard test protocolsfor in vitro dissolution are known. In some embodiments, the releaseprofile of the osmotic dosage form is characterized in that more thanabout 80% of the API is released in less than about 8 hours (e.g., about6 hours, about 4 hours), when tested by USP Dissolution Apparatus 2according to standardized and specified in USP General Chapter <711>Dissolution, at 75 rpm. In some embodiments, the release profile of thematrix dosage form is characterized in that more than about 80% of theAPI is released in less than about 8 hours (e.g., about 6 hours, about 4hours), when tested by USP Dissolution Apparatus 2 according tostandardized and specified procedures in USP General Chapter <711>Dissolution, at 100 rpm.

c. Gastric Retention Dosage Form

In some embodiments, the invention provides a gastric retention dosageform for delivering an API to a subject treated. In some embodiments,the gastric retention dosage form releases the API in the GI tract of asubject in a sustained period of time (e.g., about 2, about 4, about 6,about 8, about 10, about 12, about 14, about 16, about 18, about 20,about 22, or about 24 hours). In some aspects, the gastric retentiondosage form, by itself or in combination with a second dosage form(enterically coated immediate release or delayed release), releases theAPI in the GI tract of a subject in a pulsatile manner with a lag timefrom about 2 hours to about 14 hours (e.g., about 2 hours, about 4hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours,about 14 hours, or any ranges thereof).

In some embodiments, the gastric retention dosage form is retained inthe stomach of a subject treated, for example, has a gastric retentiontime of from about 0.2 hour to about 18 hours (e.g., about 0.2 hour,about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours,about 14 hours, about 16 hours, about 18 hours, or any ranges thereof).In some embodiments, the API in the gastric retention dosage form isretained in the stomach of a subject treated, for example, for about 0.2hour to about 18 hours (e.g., about 0.2 hour, about 0.5 hour, about 1hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours,about 18 hours, or any ranges thereof). In some embodiments, the API inthe gastric retention dosage form is retained in the stomach of asubject treated for at least 3 hours (e.g., about 3 hours, about 4hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, or anyranges thereof). In some embodiments, the API in the gastric retentiondosage form is retained in the stomach of a subject treated for about 3hours to about 17 hours. In some embodiments, the API in the gastricretention dosage form is retained in the stomach of a subject treatedfor at least 4 hours, at least 5 hours, at least 6 hours, at least 7hours, or at least 8 hours. In some embodiments, the API in the gastricretention dosage form is retained in the stomach of a subject treatedfor at least 5 hours, at least 6 hours, or at least 7 hours. Variousmeans to achieve gastric retention are known. For example, in someembodiments, the gastric retention dosage form is a floating dosage formor a swelling dosage form.

Floating Dosage Form

In some embodiments, the controlled release dosage form is a floatingdosage form that floats when exposed to gastric fluid and therebyretaining the API in the stomach of a subject treated. Varioustechniques for preparing a floating dosage form are known. In someembodiments, the floating dosage form is a floating tablet (e.g., abilayer or a trilayer tablet) or a floating capsule.

The floating dosage form described herein can include an active layerand a floating layer, wherein the active layer comprises an API (e.g.,DMF coated particles described above in the second aspect or anyembodiments described therein) and one or more release modifyingpolymers. In some embodiments, the gastric retention time of thefloating dosage form is from about 0.2 hour to about 18 hours (e.g.,about 0.2 hour, about 0.5 hour, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours,about 12 hours, about 14 hours, about 16 hours, about 18 hours, or anyranges thereof). In some embodiments, the floating dosage form floats inthe stomach until the active layer releases all the API (e.g., DMFcoated particles described above in the second aspect or any embodimentsdescribed therein). In some embodiments, the floating dosage form floatsin the stomach before the active layer releases all the API (e.g., DMFcoated particles described above in the second aspect or any embodimentsdescribed therein). The gastric retention time of the floating dosageform can be controlled by adjusting the floating layer, for example, byadjusting the amount of gas that can be generated and the speed of gasgeneration. Other techniques for adjusting the gastric retention timeare known.

Materials suitable for the floating layer include pharmaceuticalexcipients that can lower the density of the pharmaceutical composition.In some embodiments, the floating layer comprises one or more lowdensity excipients selected from the group consisting of hydroxypropylmethylcellulose, hydrogenated castor oil, carboxymethylcellulose,ethylcellulose, cross-linked povidone, chitosan and combinationsthereof. In some embodiments, the weight ratio for the one or more lowdensity excipients are adjusted such that the density of the floatingdosage form is lower than the density of the gastric fluid in a subject.

In some embodiments, the floating layer comprises a porous mineralmaterial, such as calcium silicate. In some embodiments, the porousmineral material having air entrapped within are coated with a polymer(e.g., hydroxypropylcellulose or ethylcellulose) such that the airwithin the porous mineral material is retained. In some embodiments, thefloating layer comprises a porous mineral material that furthercomprises one or more low density excipients as described herein.

In some embodiments, the floating layer comprises hollow microspheres orpolycarbonate resin that floats in a gastric fluid of a subject.

In some embodiments, the floating layer comprises a gas-generatingsystem. Suitable gas-generating systems are known in the art. In someembodiments, the floating layer comprises at least one gas-generatingsystem (e.g., a carbon-dioxide generating system, e.g., comprises analkali or alkaline earth metal carbonate or bicarbonate) and at leastone hydrophilic polymer (e.g., polysaccharide substances, proteinsubstances, poloxamers, high molecular weight polyethylene glycols,polymers of methacrylic acids, polymers of acrylic acids, derivatives ofmethacrylic acid, or derivatives of acrylic acid), a cellulose polymersuch as hydroxyalkyl alkylcellulose (e.g., hydroxypropylmethylcellulose), or a porous mineral compound (e.g., a silica or silicaderivative). In some embodiments, the floating layer comprises sodiumcarbonate and Methocel K100M. In some embodiments, the weight ratio ofsodium carbonate to Methocel K100M is from about 1:50 to about 50:1(e.g., about 1:1 to about 1:10, about 1:2 to about 1:5, or about 1:3).In some embodiment, the floating layer comprises an effervescent couple,wherein upon oral administration of the controlled release dosage formto a subject, the effervescent couple in the floating dosage formgenerates gas and causes the gastric retention dosage form to float inthe gastric liquid of the subject.

The floating dosage form described herein can take various forms. Forexample, in some embodiments, the floating dosage form is a bilayer or atrilayer tablet, wherein the floating layer and the active layer arecompressed or otherwise joined to form a tablet structure. In someembodiments, the floating dosage form is a double tablet structure,wherein the floating layer encapsulates the active layer. In someembodiments, the floating dosage form is a capsule (e.g., a soft gel orhard gel capsule) encapsulating the floating layer and the active layer.In some embodiments, the capsule is partially coated with acid insolublepolymer.

The floating dosage form described herein can be a sustained releasedosage form or a delayed release dosage form depending on theconfiguration of the active layer.

In some embodiments, the floating dosage form can be a sustained releasedosage form. For example, in some embodiments, the active layer is amatrix dosage form described herein or an osmotic dosage form describedherein.

The floating dosage form can also be a delayed release dosage form. Forexample, in some embodiments, the active layer is a delayed releasedosage form, which, when administered together with a second dosage form(e.g., an enterically coated immediate release dosage form, or a delayedrelease dosage form), provides a pulsatile release of the API with a lagtime from about 2 hours to about 14 hours (e.g., about 2 hours, about 4hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours,about 14 hours, or any ranges thereof). Suitable methods for preparing adelayed release dosage form comprising an API (e.g., coated API) includethose known. In some embodiments, the delayed release dosage form maycontain an enterically coated active layer and/or an enterically coatedAPI. In some embodiments, the delayed release dosage form comprisesabout 90% by weight of a coated API (e.g., coated DMF particles) andabout 10% by weight of a cellulose polymer (e.g., hydroxypropylmethylcellulose, Methocel E3 LV). In some embodiments, the delayedrelease dosage form may contain a core comprising an API, an inner sealcoating, followed by a semipermeable coating. In some embodiments, thedelayed release dosage form may further comprise an outer entericcoating. See examples in Example 1.

More than one active layers and/or more than one floating layers canalso be included in the floating dosage form described herein. In someembodiments, the floating dosage form comprises two floating layers. Insome embodiments, the active layer is placed between the two floatinglayers. In any of the embodiments described herein, wherein the floatingdosage form comprises three layers (e.g., two active layers one floatinglayer, or two floating layers one active layer), the floating dosageform may be a trilayer tablet or a capsule encompassing the threelayers.

In some embodiments, the floating dosage form comprises a second activelayer. In some embodiments, the second active layer is an entericallycoated immediate release dosage component, provided that the entericallycoated immediate release dosage component is not placed between theactive layer and the floating layer in a trilayer tablet structure. Insome embodiments, the floating dosage form comprises both a sustainedrelease dosage component and an enterically coated immediate releasedosage component. In some embodiments, the floating dosage formcomprises both a delayed release dosage component and an entericallycoated immediate release dosage component, wherein when administered,the floating dosage form provides a pulsatile release of the API with alag time from about 2 hours to about 14 hours.

Swellable Dosage Form

In any of the embodiments described herein, the controlled releasedosage form is a dosage form that swells when exposed to gastric fluidand thereby retaining the API (e.g., DMF coated particles describedabove in the second aspect or any embodiments described therein) in thestomach of a subject treated. Various techniques for preparing aswellable dosage form are known. For example, U.S. Pat. Nos. 5,972,389and 6,723,340 B2, incorporated by reference herein, disclose a swellabledosage form that can be utilized in the embodiments disclosed herein.

The swelling dosage form described herein can include an API (e.g., DMFcoated particles described above in the second aspect or any embodimentsdescribed therein) and one or more swelling polymer. Suitable swellingpolymers include those known in the art, for example, polyethylene oxide(e.g., Polyox 205-NF) and/or hydroxyalkyl alkylcellulose (e.g.,hydroxypropyl methyl cellulose, e.g., Methocel K4M, K100M) may be used.In some embodiments, the one or more swelling polymers are a combinationof poly(ethylene oxide) and hydroxypropyl methylcellulose in variousweight ratios (e.g., from about 10:1 to about 1:10).

In some embodiments, the swelling dosage form is a swelling tablet(e.g., a monolithic, bilayer, or trilayer tablet) or a swelling sheet(e.g., an Accordion Pill™, in which an API, optionally coated, isembedded in one section of the swellable polymer sheets). In someembodiments, the swelling dosage form is a monolithic tablet comprisingan active layer comprising an API (e.g., DMF coated particles describedabove in the second aspect or any embodiments described therein) and aswelling layer. In some embodiments, the swelling layer encapsulates theactive layer. In some embodiments, the swelling dosage form is a bilayertablet comprising an active layer comprising an API (e.g., DMF coatedparticles described above in the second aspect or any embodimentsdescribed therein) and a swelling layer. In some embodiments, more thanone active layer are present in the swelling dosage form. In someembodiments, more than one swelling layer are present in the swellingdosage form.

The swellable dosage form herein may be a sustained release or delayedrelease dosage form.

In some embodiments, the swelling dosage form is a sustained releasedosage form. In some embodiments, the API together with the swellingpolymer form a swellable matrix. In some embodiments, the API is coated(e.g., seal coated, enterically coated, or a combination thereof). Insome embodiments, the API in the swellable dosage form may be in anamount of about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, or any ranges thereof, by weight of total weight of theswellable dosage form. The one or more swelling polymers in theswellable dosage form may be in an amount of about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,or any ranges thereof, by weight of total weight of the swellable dosageform. The swellable dosage form may also include pharmaceuticalexcipients in an amount of about 0.1%, about 0.5%, about 1%, about 2%,about 5%, about 10%, or any ranges thereof, by weight of total weight ofthe swellable dosage form. For example, the swellable dosage form may becomposed of about 60% coated DMF; about 24% Polyox 205-NF (PEO); about15% Methocel K4M (HPMC); and about 1% magnesium stearate.

In some embodiments, the swellable matrix releases the API in asustained manner over a period of from about 2 to about 24 hours (e.g.,about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours,about 20 hours, about 22 hours, about 24 hours, or any ranges thereof).In some embodiments, the swellable matrix exhibits zero-order release ofthe API.

In some embodiments, the swelling dosage form is a delayed releasedosage form, which, when administered together with a second dosage form(e.g., an enterically coated immediate release dosage form, or a delayedrelease dosage form), provides a pulsatile release of the API with a lagtime from about 2 hours to about 14 hours (e.g., about 2 hours, about 4hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours,about 14 hours, or any ranges thereof). In some embodiments, theswellable pulsatile release dosage form comprises one or more swellingpolymers and an API. In some embodiments, the API is coated (e.g., sealcoated, enterically coated, or a combination thereof). Suitableswellable polymers are described above.

In some embodiments, the swelling dosage form comprises both a delayedrelease dosage component and an enterically coated immediate releasedosage component, wherein when administered, the swelling dosage formprovides a pulsatile release of the API with a lag time from about 2hours to about 14 hours.

Folded Dosage Form

In certain embodiments, the controlled release dosage forms of thepresent invention are folded dosage forms as those described in U.S.Pat. Nos. 6,685,962, 8,609,136 and 8,771,730, the entire teaching ofwhich is incorporated herein by reference.

In a first embodiment, the folded dosage form of the present inventionis a folded device configured for unfolding from a folded configurationfor oral intake to an unfolded configuration for gastric retention,wherein the device comprises:

two external layers sandwiching a functional layer therebetween;

the functional layer comprises DMF;

the functional layer being configured for imparting mechanical strengthto the device sufficient to enable, upon unfolding of the device, thepreservation of said unfolded configuration to provide gastricretention.

In one embodiment, the DMF in the functional layer is DMF coatedparticles described in the second aspect or any embodiments describedtherein.

In another embodiment, the DMF in the functional layer is DMF withoutenteric coating. In certain embodiments, when non-enterically coated DMFis used in the functional layer, the device can further comprise twoenteric layers sandwiching the functional layer therebetween and the twoexternal layers are located on the outside of the enteric layer.Alternatively, the non-enterically coated DMF can be embedded into anenteric layer. In another embodiment, the non-enterically coated DMF isembedded into the functional layer comprising one or more entericpolymers.

The enteric layer comprises one or more enteric polymer describedherein.

In one embodiment, at least one of the external layers comprisesperforations. Alternatively, both external layers comprisesperforations.

In some embodiments, the folded device is folded parallel to one of thesides of the unfolded laminated/integrated device. In some embodiments,the folded dosage component has folds of increasingly smaller amplitudesupon extending away from the middle thereof so as to have an overallrounded cross section and to allow the folded device to be easilyinsertable into a container (envelop, e.g. capsule).

In some embodiments, the functional layer comprises a matrix furthercomprising one or more layers and a pharmaceutical compositioncomprising the DMF coated particles of the present invention, whereinDMF is releasable from the matrix. In some embodiments, the matrixcomprises a polymer or polymer combination that is insoluble in gastriccontent. In some other embodiments, the functional layer may comprise acombination of compartments enclosing a pharmaceutical compositioncomprising the DMF coated particles and a matrix embedding the DMFcoated particles.

In some other embodiments, the matrix comprises at least one solublepolymer or a soluble combination of polymers in combination with atleast one insoluble polymer (or insoluble combination of polymers).

In some embodiments, the functional layer does not release DMF or DMFcoated particles in the stomach. In one embodiment, the functional layerreleases less than 20%, less than 15%, less than 10%, less than 5% orless than 1% of DMF coated particles in the stomach.

Alternatively, the functional layer releases DMF coated particles in thestomach over a long period time, such as 8-20 hours, 8-15 hours or 8-12hours. In one embodiment, the functional layer releases 70-100%,80-100%%, or 90-100% of DMF coated particles from the internal layerover 4-20 hours, over 8-20 hours, over 8-12 hours or over 4-8 hours.

The one or more layers may also comprise a layer of an enforcingpolymeric composition so as to provide the desired configuration of thesingle or multi-layered device, once unfolded (e.g. following wetting bygastric content or by a medium resembling gastric content). The desiredconfiguration may be achieved by the incorporation of an enforcingpolymeric composition having a mechanical strength enabling, uponwetting and unfolding of the device, the preservation of the unfoldedconfiguration of the device, i.e. after ingestion. The enforcingpolymeric composition may be provided over DMF carrying layer (e.g.polymeric matrix), over the compartments comprising DMF, and/or may beintegrally formed with or in the DMF layer.

According to one embodiment, the enforcing polymeric composition is inthe form of one or more continuous or non-continuous polymer strips. Forexample, the strips may define a continuous or non-continuous frame atsaid device's periphery. The continuous or non-continuous frame may beeither affixed or attached to the matrix or integrally formed with thematrix. Further, when as a strip or in a continuous form to form theso-called frame, the enforcing strip/frame may comprise a single orplurality of defects, e.g. gaps, depressions or slits, typically alongthe width of the strip/frame. Without being bound by theory, it isbelieved that such slits are essential for providing breakable areasalong the strip/frame such that after a pre-determined time (e.g. whenexpulsion of the device from the body is desired, for example, after 12hours) the areas containing the slits weaken and break, resulting in thedisintegration of the device and its eventual removal from the stomachthrough the pylorus sphincter.

The combination of the enforcing composition, polymeric matrix and thepharmaceutical composition comprising DMF or DMF coated particles (orcollectively as the pharmaceutical DMF composition) constitute, attimes, the functional layer (the functionality denoting that thesecombined layers constitute a significant functional portion of thedevice, on the one hand, the gastro-retentivity, established by theenforcing layer, and the active principle ingredient, i.e. DMF, on theother hand). According to this embodiment, the assembly step maycomprise assembling at least one layer of the enforcing composition,e.g. in a form of one or more continuous or non-continuous strips, withone or more layers comprising the DMF pharmaceutical composition or withthe DMF pharmaceutical composition enclosed within the enforcing strips.

In accordance with one embodiment, the strips are in the form of a framehave inner boundaries defining a void, and the method comprisesassembling the frame with one or more layers comprising thepharmaceutical DMF composition, such that the one or more layerscomprising the pharmaceutical DMF composition is affixed, attached orintegrally formed within said void. Alternatively or in addition, thepharmaceutical DMF composition may be enclosed, at least partially,within the frame.

The pharmaceutical DMF composition may be contained in the device invarious forms. The incorporation of the pharmaceutical DMF compositionthereof in the device is carried out in the assembly step. Thus, inaccordance with an embodiment of the invention, the assembly stepcomprises at least one of the following: embedding the pharmaceuticalDMF composition into one or more layers or into one or more compartmentswithin one or more layers (e.g. a single layer may comprise areas ofdifferent composition of the polymer material forming it thereby formingdistinguishable areas/compartments within the layer and thesecompartments may differently carry/release DMF so as to provide adifferential release profile of DMF from the device); trapping thepharmaceutical DMF composition within at least two layers (e.g. suchthat the layers form a pouch housing the agent); enveloping thepharmaceutical DMF composition within at least one polymeric membranesegment; attaching said pharmaceutical DMF composition to or in at leastone of said one or more layers of the device, or to a carrier, thecarrier may be in the form of nano- or microspheres, nano- ormicrocapsules comprising particulate matter (i.e. a matrix)accommodating the active agent (by embedding, entrapping or having theagent affixed to the particulate's outer surface), beads coated orimpregnated with the active agent, granules, pellets and compressedtablets.

In order to provide the desired mechanical strength in situ, once thedevice is in an unfolded state in the stomach, it is preferable that theenforcing polymeric composition, or at least one other layer of thedevice comprises a polymer that is insoluble in gastric juices/content.Alternatively, the mechanical strength can be provided by a combinationof enteric and non-enteric insoluble polymers.

In addition to the aforementioned composition, the enforcingcomposition, irrespective of its shape or its number (e.g. number ofstrips made of the enforcing composition) within the device may furthercomprise a polymer, soluble in gastric content, which is eitherentrapped in the insoluble composition or is cross-linked in such waythat it does not exude from the insoluble composition and can not beextracted without disintegrating the whole frame.

In accordance with a preferred embodiment, the device is a laminateddevice comprising two external layers made of a first material andsandwiching one ore more layers comprising one or more strips made of asecond material and comprising the pharmaceutical DMF composition. Theexternal sheets may comprise one or more polymers selected from thegroup consisting, without being limited thereto, polymers soluble ingastric content, polymers insoluble in gastric content, and acombination of any two or more thereof.

Nonetheless, in accordance with some other embodiments, the laminateddevice comprises two external layers made of a first material andsandwiching one ore more layers comprising one or more strips made of asecond material, such that the one or both external layers comprise thepharmaceutical DMF composition. In the context of this embodiment, thepharmaceutical DMF composition may be embedded in as well as depositedto the outer surface of one or both external layers, e.g. by inkjetprinting. An ink jet technology that has been developed is such thatallows the preparation of poly(lactic-co-polycolic acid) (PLGA)microspheres with uniform particle size distribution [Radulescu D et al.Uniform paclitaxel-loaded biodegradable microspheres manufactured by inkjet technology Proceedings of the Winter Symposium and 11.sup.thInternational Symposium on Recent Advances in Drug Delivery Systems SaltLake City, Utah, USA (2003)]. These microspheres while carrying theagent may then be affixed or attached to the one or both externallayers.

In accordance with one embodiment, the external layers comprise apolymer or polymer composition that is soluble in gastric content. Inanother embodiment, the external layers are degradable in intestine.

According to another embodiment, the external layer is comprised of amixture of a soluble polymer and an enteric polymer. According toanother embodiment, the external layer comprises a cross-linked watersoluble polymer, e.g. a soluble polymer cross-linked withglutaraldehyde, or an enzymatically hydrolyzed cross-linked gelatin anda derivative thereof.

Another example of external layer composition can be polyvinyl alcoholfilm, cross-linked with glutaraldehyde. Alternatively, said polyvinylalcohol film could be subjected to one or more freeze-thaw cycles toinduce crystallization.

Yet another example of external layer composition can be polyethyleneoxide film, cross-linked by gamma irradiation.

In addition to the mentioned composition, the layers independently maycomprise fillers, lubricants, plasticizers and other pharmaceuticallyacceptable processing adjuvants.

In some embodiments, one or more external layers comprise perforations.In one embodiment, both external layers of the device compriseperforations. The perforations may be generated before the layers areintegrated into the device; as a sub-step in the assembly step orfollowing the assembly step (i.e. after all layers are assembledtogether into a whole unit), however, before the folding step; or theexternal layers may constitute a combination of materials such that whenthe device is wetted (or at least the external layers), perforations areproduced. The dimensions, distribution pattern, shape and amount ofperforations may vary between one device to another, within a layer of asingle device as well as between the two external layers of a device,depending on the specific design of the device and the manner of theirformation (e.g. mechanical slicing of holes or perforations resultingfrom dissolution of a component of the external layer following wettingby gastric content).

The perforations may be achieved by the use of a perforation apparatushaving an array of pins or slicing knives presses against the layer tobe perforated. As indicated above, the perforations may be of variousdimensions and distribution patterns, and may be different between thetwo external layers. To this end, the perforation apparatus may comprisea series of differently arranged array of pins, the pins (or knives)being of the same or different dimensions etc.

In some embodiments, perforations comprise a plurality of holes. Inother embodiments, perforations comprise a plurality of pores.

The assembly of the device's layers may be facilitated by variousintegration/lamination techniques known to those in the art, such asthose described in the U.S. Pat. No. 8,609,136.

The assembly of the device's layers may be facilitated by variousintegration/lamination techniques known to those versed in the art. Theassembly may be achieved by applying onto at least portions of some ofthe layers an integration agent, prior to bringing the respective layersinto contact. The coating may be on one or more layers. A particularexample includes application to at least one surface of the externallayers, the strip/frame and the layer carrying the agent oragent-releasing formulation.

In accordance with one embodiment, the integration agent is an adheringagent which may be sprayed onto at least some of the layers of thedevice. In accordance with this embodiment, the adhering agent ispreferably an organic solvent, a mixture of organic solvents, or amixture of organic and water-based solvents such as salt solutions. Morepreferably the organic solvent is ethanol or mixture of ethyl acetateand ethanol.

In accordance with some other embodiments, the assembly is facilitatedby other techniques such as welding (heat-welding, welding by highfrequency, welding by ultrasound etc.), by curing (e.g. heat curing),fusion or any other technique involving melting both layers to formadherence at the interface between the layers as well as pressing thelayers together (with or without heating to temperatures aboveroom/ambient temperature). The said other techniques may involve the apriori application of an agent or substance to the layer so as tofacilitate the assembly, as appreciated by those versed in the art.

In another preferred embodiment, the composition of the outer layer istreated so as to modify the properties of the outer surface, e.g. so asto prevent adhering of the undulated surface of the device as a resultof folding. To this end, the assembly step may further comprise coatingof the outer surface of one or both external layers with ananti-adhering coating, e.g. powder coating, polymer coating, liquidspray coating, dispersion (latex) coating, etc. The application of thepowder may involve the a priori application of an adhering agent asdefined above so as to facilitate adherence of the powder coating ontothe respective layer.

In accordance with one preferred embodiment of the present invention,there is provided a method for producing a laminated device, preferablya gastro-retentive dosage form, comprising: (i) assembling a laminateddevice that comprises: a) a first external layer made of a first,typically polymeric material; b) a frame of a second, typicallypolymeric, material mounted on the first external layer; c) adrug-releasing formulation housed within the frame; and d) a secondexternal layer made of the first material and mounted on the frame; and(ii) folding the laminated device into a folded device; and (iii) atleast partially enclosing the folded device to produce the deliverydevice, preferably gastro-retentive dosage form, that can beadministered orally.

In some preferred embodiments, the frame comprises one layer. In otherembodiments, the frame comprises two or more layers. In accordance withone, non-limiting, embodiment, the frame has a thickness of around 400microns, independent of the number of layers therein.

Further, in accordance with some other embodiments, the invention isdirected to a method for producing an oral agent-releasing dosage form,comprising: (i) preparing or providing two first, essentially planar,polymeric sheet portions made of a first polymeric material that whenwetted is permeable to the active agent, and a having outer boundaries;(ii) preparing or providing a second, essentially planar, polymericsheet portion made of a second polymeric material defining a frame withouter boundaries and inner boundaries, the outer boundaries being ofessentially the same shape as the outer boundaries of the firstpolymeric sheet portion and the inner boundaries defining a void area;(iii) preparing or providing a third, essentially planar, polymericsheet portion made of a third polymeric sheet comprising an agent oragent releasing formulation releasable from the third sheet when incontact with an aqueous medium and defining a drug-containing andreleasing matrix, said matrix having outer boundaries to fit within thevoid area; (iv) assembling the four portions such that said third sheetis placed within the void area and the two (the second sheet portion andthe third sheet portion) being jointly sandwiched between the two firstpolymeric sheet portions, with all the outer boundaries essentiallyoverlapping one another thus yielding a laminated device; (v) foldingthe laminated device into a form to fit into a capsule, and inserting itwithin a capsule made of a material that dissolves in the gastricfluids.

In some cases, this method comprises preparing first, second and thirdpolymeric sheets made of the first, second and third polymericmaterials, respectively, and cutting out the respective first, secondand third polymeric sheet portions therefrom such that all sheets haveessentially the same outer shape so as to facilitate the overlap betweenthe outer boundaries thereof.

Yet further, in accordance with another embodiment, a method forproducing an agent delivery device, comprising: (i) assembling an agentor an agent-releasing formulation within a generally planar assembly toform an integrated or laminated device, wherein the generally planarassembly may comprise a single or plurality of layers and may compriseor consist of a frame; (ii) manipulating the integrated or laminateddevice into a compacted integrated device, wherein the projected surfacearea of the compacted laminated dosage form is at least five times lessthan that of the integrated device; and (iii) at least partiallyenclosing the compacted device to produce the gastro-retentive dosageform.

In accordance with this embodiment, the projected surface area of thecompacted device may also be at least six times, at least seven times,at least eight times, at least nine times and even at least ten timesless than that of the integrated/laminated device form. The agent/agentreleasing formulation may be assembled as part of a layer carrying thesame and surrounded, at least partially, by the frame. Further, thegenerally planar assembly may comprise one or more external layers. Apreferred embodiment in accordance with this method concerns a generallyplanar assembly comprising at least three integrated/laminated layers.

Further, in accordance with another embodiment of the present invention,the assembling step comprises introducing the agent or agent-releasingformulation into a layer of a second material (different from thematerial forming the external layers and/or the strips/frame).

Additionally, in accordance with another embodiment of the presentinvention, the folding step comprises: mounting the laminated devicebetween two opposite faces of a press, each of which constituting ablock having corrugated surface with ridges of one being essentiallyopposite to troughs of the other and essentially fitting one into theother; and pressing the two opposite faces one versus the other so as toform an undulated, three-dimensional device, wherein the undulationsthereof correspond to the shape of the corrugated surface.

In another preferred embodiment, the folding step further comprisesapplying a force so as to press the undulated device from two sides andin a direction perpendicular to the undulations, into a folded devicehaving folds formed along ridges and troughs of the undulations.

In some preferred embodiments, the folded device is folded parallel toone of the sides of the unfolded laminated/integrated device. In anotherpreferred embodiment, the folded device has folds of increasinglysmaller amplitudes upon extending away from the middle thereof so as tohave an overall rounded cross section and to allow the folded device tobe easily insertable into a container (envelop, e.g. capsule).

Thus, in accordance with the latter preferred embodiment, the twoopposing surfaces of the press have such corrugations that followingpressing, undulations with amplitudes that decrease from the middletowards the ends are formed, and upon the subsequent pressing in thesaid perpendicular direction an essentially circular cross-section iseventually attained, thus having an overall cylindrical form with alongitudinal axis parallel to the folds.

In one preferred embodiment, the eventual cross-section is such to allowthe insertion of the folded device into a capsule of a kindconventionally used in pharmaceutical dosage forms. In accordance withthis latter embodiment the process preferably further comprises at leastpartially enclosing the folded device within a capsule by pushing italong the longitudinal axis into one half of a capsule.

In accordance with a preferred embodiment of the present invention, theat least partially enclosing step of the above embodiment comprises:

placing the folded device into a capsule base (i.e. one half of thecapsule before enclosure); and

fitting a capsule cap (i.e. the other half of the capsule) onto thecapsule base so as to form an encapsulated folded integrated deliverydevice/dosage form.

In some other embodiments, the folded device is at least partiallyenclosed within an enclosure through at least one process selected from:wrapping (e.g. with a polymeric thread), dipping (e.g. to form mold),spraying (e.g. with a polymeric coating material), encapsulating,binding (e.g. with a polymeric thread), tying (e.g. with a polymericthread), molding (e.g. to form mold), enveloping and sealing.

In a second embodiment, the folded dosage form of the present inventionare biodegradable, multi-layered gastroretentive dosage forms that havesustained release of DMF in the GI tract as described in U.S. Pat. No.8,771,730.

In one embodiment, the folded dosage form comprises an internal layercontaining DMF or DMF coated particles of the present invention (e.g.,as described in the second aspect and any specific embodiments describedtherein) and a degradable polymer which is not instantly soluble ingastric fluid. The internal layer includes a first side and an opposingsecond side. At least one membrane is covering the internal layer. Themembrane comprises at least one polymeric combination of a hydrophilicpolymer and a polymer, insoluble in gastric media, the membrane beinghydratable in the gastric media. The membrane is directly secured to andcovers both sides of the internal layer and has a predetermined lengthgreater than 20 mm in a planar orientation, the membrane and internallayer being arranged in an accordion folded orientation sufficientlycompact to be placed within a capsule dissolvable within the stomach ofa patient and simulated gastric media. The membrane and internal layerunfold from the accordion folded orientation to a length of at least 20mm within 30 minutes of being exposed to gastric media. The membranepermits passage of gastric media from the environment to the internallayer and permits passage of the active agent from the internal layerthrough the membrane to the environment.

In another embodiment, the folded dosage form of the present inventioncomprise an internal layer comprising DMF or DMF coated particles of thepresent invention (e.g., as described in the second aspect and anyspecific embodiments described therein) and a degradable polymer whichis not instantly soluble in gastric fluid. A first and second membranescover the internal layer, the membranes including at least one polymericcombination of a hydrophilic polymer and a polymer, insoluble in gastricmedia and the membranes being hydratable. The first and second membranesare having a width and length greater than a width and length of theinternal layer. The first and second membranes are being ultrasonicallywelded or otherwise affixed or attached directly together about theperiphery of the first and second membranes. The first membrane is beingultrasonically welded to a first side of the internal layer, the secondmembrane is being ultrasonically welded to the second side of theinternal layer. The ultrasonically welded internal layer and first andsecond membranes have a predetermined length greater than 20 mm in aplanar orientation, the membrane and internal layer being arranged in anaccordion folded orientation sufficiently compact to be placed within acapsule dissolvable within the stomach or simulated gastric media. Theultrasonic welds having sufficient mechanical strength and stability toremain intact when being exposed to gastric fluid.

In still another embodiment, the folded dosage form of the presentinvention comprises an internal layer comprising DMF or DMF coatedparticles of the present invention (e.g., as described in the secondaspect and any specific embodiments described therein) and a degradablehydrophilic polymer which is not instantly soluble in gastric fluid anda degradable enteric polymer which is substantially insoluble at pH lessthan 5.5, and optionally a plasticizer. At least one membrane covers theinternal layer, the membrane includes at least one polymeric combinationof a hydrophilic polymer and a polymer, insoluble in gastric media, andat least one plasticizer. The membranes swell in the presence of gastricfluid. At least one of the materials in each of the internal layer andmembranes are being capable of being ultrasonically welded together. Themembrane is directly secured to and covers both sides of the internallayer and has a predetermined length greater than 20 mm in a planarorientation. The membrane and internal layer are being arranged in anaccordion folded orientation sufficiently compact to be placed within acapsule dissolvable within the stomach or in simulated gastric media.The membrane permits passage of gastric media from the environment tothe internal layer and permits passage of the active agent from theinternal layer through the membrane to the environment. The membrane andinternal layer unfold from the accordion folded orientation to a lengthof at least 20 mm within 30 minutes of being exposed to gastric fluid.

In still another embodiment, the folded dosage form of the presentinvention comprises an internal layer comprising DMF or DMF coatedparticles of the present invention (e.g., as described in the secondaspect and any specific embodiments described therein) and a degradablehydrophilic polymer which is not instantly soluble in gastric fluid anda degradable enteric polymer which is substantially insoluble at pH lessthan 5.5, and a plasticizer. First and second membranes cover theinternal layer, the membranes include at least one polymeric combinationof a hydrophilic polymer and a polymer, insoluble in gastric media, andat least one plasticizer. The membranes swell in the presence of gastricfluid. At least one of the materials in each of the internal layer andmembranes are being capable of being ultrasonically welded together. Themembranes being directly secured to and covering both sides of theinternal layer and having a predetermined length greater than 20 mm in aplanar orientation, the membranes and internal layer being arranged inan accordion folded orientation sufficiently compact to be placed withina capsule dissolvable within the stomach. The membranes and internallayer unfold from the accordion folded orientation to a length of atleast 20 mm within 30 minutes of being exposed to gastric fluid. Thefirst and second membranes have a width and length greater than a widthand length of the internal layer. The first and second membranes areultrasonically welded or otherwise affixed or attached directly togetherabout a periphery of the first and second membranes. The first membraneis ultrasonically welded to a first side of the internal layer. Thesecond membrane is ultrasonically welded to the second side of theinternal layer. The membrane permits passage of gastric media from theenvironment to the internal layer and permits passage of the activeagent from the internal layer through the membrane to the environment.The ultrasonically welded internal layer and first and second membraneshave a predetermined length greater than 20 mm in a planar orientation.The membrane and internal layer being arranged in an accordion foldedorientation sufficient to be placed within a capsule dissolvable withinthe stomach. The ultrasonic welds having sufficient mechanical strengthand stability to remain intact when being exposed to gastric fluid.

In one embodiment, the gastroretentive drug formulations are for thesustained release of DMF in the gastrointestinal tract and comprise: i.)an internal layer or compartment comprising the DMF coated particles (asdescribed in the second aspect or any embodiments therein) and one ormore pharmaceutical excipients, of which at least one is a polymer; ii.)two membranes forming together an envelope around the inner membrane,each comprising at least one polymeric combination of a polymer which isnot soluble in gastric juice, and a hydrophilic swelling polymer, and atleast one plasticizer; and iii.) optionally an additional layer coveringeach outer membrane comprising a powder or a film that preventsadherence of the outer membrane onto itself when folded inside thecapsule.

In preferred embodiments, the gastroretentive drug formulationseffectively unfold and retain their mechanical integrity in acidic pHfor up to 24 hours and completely biodegrade after 3 hours in simulatedintestinal fluid.

In one aspect, the polymer in the internal layer is a degradable polymerwhich is not instantly soluble in gastric fluid. In another aspect, thepolymer is a degradable enteric polymer which is substantially insolubleat pH less than 5.5. The invention also contemplates mixtures ofpolymers as described above.

In one embodiment, the enteric polymer in the internal layer ispolymethacrylate copolymer. In different embodiments, the entericpolymer is cellulose acetate phthalate, or hydroxypropylmethyl cellulosephthalate, or hydroxypropyl methyl cellulose acetate succinate. In apreferred embodiment, the DMF coated particles described above in thesecond aspect or any embodiments described therein and the polymer aresubstantially uniformly distributed in the internal layer.

In another embodiment, the polymeric combination of the outer membranescomprises gelatin and hydroxypropyl methyl cellulose acetate succinateas enteric polymer. In one embodiment, the enteric polymer in the outermembranes is polymethacrylate copolymer type A. In a differentembodiment, the enteric polymer in the outer membranes ispolymethacrylate copolymer type C. In a further embodiment, theplasticizer in the outer membranes is propylene glycol.

In a preferred embodiment, the internal layer or compartment, the outermembranes and the optional additional layers are sealed by applyingultrasonic welding.

In an additional embodiment, the internal layer provides at least 50% ofthe mechanical strength of the whole gastroretentive drug formulationswhen wetted with gastric fluid. In a preferred embodiment, thegastroretentive drug formulation reaches its maximum strength within onehour in simulated gastric fluid. In yet another preferred embodiment,the internal layer has a planar-accordion geometry that unfolds to atleast 50% of its original length within 30 minutes in gastric media.

In one aspect, the gastroretentive drug formulation is fully degradablewithin 3 hours in simulated intestinal fluid. In an additional aspect,the gastroretentive drug formulation provides gastric retention for upto 24 hours under low or medium calorie diet. In yet another aspect, thegastroretentive drug formulation moves in the stomach during gastricretention.

The gastroretentive drug formulations are designed for oraladministration and are compacted or folded into a standard size capsulewhich is easily swallowed. The active ingredient DMF is incorporated inthe gastroretentive drug formulations as dissolved matter in compositionof the formulation, powders, grains, spheres, particles, microparticles,nanoparticles, multiparticulates, tablets or microcapsules.

In one embodiment, the gastroretentive drug delivery system includes aninternal layer and an outer layer. The outer layer is formed from twofilms which are slightly larger than the internal layer and which aresealed or welded together around their perimeter and completely envelopethe internal layer. Along with welding which connects the outer layerstogether, the outer portion of the internal layer is also welded to theouter layers.

Alternatively, the gastroretentive drug delivery system includes aninternal layer and an outer layer, whereas the outer layer is formedfrom two membranes which are equal in size with the internal layer andwhich are sealed or welded together around their perimeter and the outerportion of the inner layer. Optionally the gastroretentive deliverysystem comprises an additional layer which is either larger or equal insize to the inner/outer membranes assembly, and envelops the assembly toprevent adhesion of the membranes onto themselves; the said layer can beformed with one or more membranes, ultrasonically welded or otherwiseattached or affixed onto the assembly, and can optionally comprise anAPI. The ultrasonically welded or otherwise attached internal layer andouter layers are folded in an accordion arrangement and placed within acapsule. In some embodiments, the capsules are made from gelatin orhypromelose. The layers are shaped in essentially oval polygonal formsuch that they maximize the amount of space within the capsule that isfilled. Once the gelatin or hypromelose capsule dissolves within thegastric medium, the internal layer and outer layers expand from theaccordion folded orientation to a more planar orientation.

The gastroretentive drug formulations of the present invention markedlyimprove absorption and bioavailability of DMF due to its ability towithstand peristalsis and mechanical contractility of the stomach, andconsequently, release the drug in a controlled manner onto itsabsorption sites and without premature transit into non-absorbingregions of the GI tract. The gastroretentive drug formulation canprovide gastric retention of DMF having a narrow absorption window forup to 24 hours under low or medium calorie diet. In addition,administration of these formulations to a mammal can improve thepharmacokinetic and pharmacodynamic properties of DMF. Since thegastroretentive drug formulations are fully degradable, they provide ameans to administer the proper dose of the drug without generatingnon-degradable residues that would not be eliminated after drug release.

The gastroretentive drug formulations are stable, fully degradable andprovide efficient delivery of DMF in the gastrointestinal tract due tothe combination of an internal layer having planar-accordion geometrywhere all components are fully biodegradable. The combination ofswelling outer membrane layers with a substantially non-swellinginternal layer having planar accordion geometry causes the internallayer to undergo an unfolding process once the formulation reaches thestomach, thus extending gastric residence time and preventing the dosageform from being evacuated until substantial or complete release.

Sustained-Release Gastroretentive Drug Formulations

In one embodiment, the present invention provides a stable, degradable,multi-layered gastroretentive drug formulation for the sustained releaseof DMF in the gastrointestinal tract. The gastroretentive drugformulation comprises: i.) an internal layer or compartment comprisingDMF coated particles of the present invention (e.g., as described in thesecond aspect and any specific embodiments described therein), one ormore polymers and one or more modifying agents such as plasticizersand/or solubilizers and/or fillers; ii.) two outer membranes, eachcomprising at least one polymeric combination of hydrophilic polymer anda polymer insoluble in gastric media, and at least one plasticizer; andiii.) optionally an additional layer covering each outer membrane andcomprising a powder or a film that prevents adherence of the outermembranes to itself.

In accordance with another embodiment of the invention, degradable,multi-layered gastroretentive drug formulation for the sustained releaseof DMF can be combined with one or more immediate release layerscovering the outer membranes and comprising DMF (e.g., DMF coatedparticles of the present invention, such as those described in thesecond aspect and any specific embodiments described therein) and apolymer and optionally other excipients, known in the art, that providesfor the immediate release of DMF to form degradable, multi-layeredgastroretentive drug formulation for combined immediate-release andsustained-release of DMF. Optionally an additional layer covering eachouter membrane and comprising a powder or a film that prevents adherenceof the outer membranes to itself is included. Additional disclosureregarding the immediate and controlled release formulations are providedbelow.

a) Internal Layer

The internal layer or compartment in the gastroretentive drugformulations comprise the DMF coated particles of the present invention(e.g., those described in the second aspect and any specific embodimentsdescribed therein) and a polymer substantially uniformly distributedthroughout the internal layer. The polymer can be a degradablehydrophilic polymer which is not instantly soluble in gastric fluid, adegradable enteric polymer which is substantially insoluble at pH lessthan 5.5, a hydrophobic polymer or mixtures thereof. It can furthercomprise acceptable pharmaceutical additives, such as plasticizers,humectants, fillers and others.

Examples of degradable hydrophilic polymers which are not instantlysoluble in gastric fluid suitable for the invention are hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone,polyethylene oxide and methylcellulose. Preferably, the enteric polymeris a polymethacrylate copolymers, cellulose acetate phthalate,hypromelose acetate succinate or hypromellose phthalate. These polymersare combined with the DMF coated particles of the present invention(e.g., those described in the second aspect and any specific embodimentsdescribed therein).

Preferably, the internal layer has planar accordion geometry. Thisfeature, together with the presence of polymers as described above inthe internal layer or compartment provides the internal layer withsubstantial mechanical strength. Preferably, the internal layer has amechanical strength with Young's modulus of from about 0.5 to 15Kgf/mm². Preferably, the range could be from about 3.0 to about 10.0Kgf/mm² or from about 3.0 to about 6.0 Kg f/mm². The stress may rangefrom about 0.03 to about 0.6 Kgf/mm² after 1 hour in simulated gastricfluid, such that the gastroretentive drug formulation reaches itsmaximum strength within one hour in simulated gastric fluid.Alternatively the range for stress may be from about 0.05 to about 0.4Kgf/mm² or about 0.1 to about 0.4 Kgf/mm².

The components of the internal layer may be altered. In some instances,the internal layer does not allow effective welding between the outerand internal layer. In such situations, the internal layer may becomposed of the two or more portions, where each portion has definitefunction. In one instance, the central region (welding free) can beformulated as separate film to hold the active ingredient and be placedinto the central portion and over the inner film comprising anadditional portion that will support this central portion. Thisadditional portion can then be welded to the outer layer. In anotherinstance, whereas the internal layer cannot be formulated to develop thenecessary mechanical strength in the gastric medium, at least oneadditional layer, optionally comprising no drug, could be used as ascaffold, whereupon the formulated drug reservoir film could be laid andwelded or otherwise attached or affixed, onto one or both sides of saidbackbone, and the assembly could be welded to the outer membranes andother components of the delivery system.

b) Outer Membranes

Each of the outer membranes in the gastroretentive drug formulationscomprises at least one polymeric combination of a hydrophilic polymerand a polymer, insoluble in gastric media, and at least one plasticizer.

Examples of suitable ingredients for the invention include gelatin,hydroxypropylcellulose, hydroxypopyl methycellulose, pectin,polyethylene oxide, starch, and zein. Preferably, the hydrophilicpolymer is gelatin. The amount of gelatin in each of the outer membranesis between about 20 and about 45% of the total outer membranecomposition, and preferably between about 25 and about 35% of the totalouter membrane composition.

Examples of enteric polymers that can be used in the outer membranesinclude hypromellose phthalate, hypromellose acetate succinate andpolymethacrylate co-polymers. Preferably, the enteric polymer ispolymethacrylate copolymer type A or polymethacrylate copolymer type C.

Plasticizers suitable for the invention include various polyethyleneglycols, glycerin, triethylcitrate. Preferably, the plasticizer ispropylene glycol.

The outer membranes swell in the presence of gastric fluid and are fullydegradable within two hours in simulated intestinal fluid. Thecombination of swelling outer membrane layers with a non-swellinginternal layer having planar accordion geometry causes the internallayer to undergo an unfolding process once the formulation reaches thestomach, thus extending gastric residence time and preventing thedrug-containing dosage form from being evacuated until complete release.In one embodiment the internal layer has a swelling rate less than theswelling rate of the membrane.

The membrane permits passage of gastric medium from the environment tothe internal layer and permits passage of the DMF coated particles fromthe internal layer through the membrane to the environment.

In some instances the kinetics of such transport can be unacceptablylow. Therefore in some embodiments the outer membranes can be perforatedwith one or more orifices to facilitate the mass transfer processesthrough the membrane. In preferred embodiments the orifices areuniformly distributed over the area hereabout the formulated drug layer.

c) Optional Additional Layer

The gastroretentive drug formulations of the invention may furthercomprise an optional additional layer covering each outer membrane andcomprising a powder or a film. In some instances it may be found thatthe outer layers stick together in the capsule and do not unfoldproperly upon dissolving of the capsule. In such situations, thisoptional layer prevents adherence of the outer membranes to themselvesand allows for the proper opening of the GRDF. In preferred embodiments,the optional layer comprises at least one powder, and optionally atleast one polymer. In other embodiments the preferred polymers arerapidly-dissolving film formers, which can be selected from but notlimited to soluble cellulose derivatives, i.e. methyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose; variousgrades of povidone; polyvinyl alcohol and its derivatives, i.e.Kollicoat IR; soluble gums and others. The films may further comprisesurface-active agents, plasticizers and humectants.

Ultrasonic Welding

The internal layer or compartment, the outer membranes, the optionallayers and/or the immediate release layers may be attached to each otherby many means. Preferably, they are sealed by applying ultrasonicwelding. One example of a device suitable for these purposes is theDynamic 745 ultrasonic welder from Rinco Ultrasonics, but other devicesmay be employed. The welding effectively seals the internal layer withinthe outer layer by welding the outer layers together and also weldingthe perimeter of the internal layer to the outer layer. It can alsoefficiently attach the layers to one another without sealing a wholeenvelope, meaning that there is no need for same-material welding,should the formulations be compatible.

Different patterns and times may be used for the welding based on theneeds of those skilled in the art. Although the periphery of the layerscan be welded together, the current embodiments do not weld the centralportion of the GRDF device so as to minimize any heating or effects onthe majority of the internal layer which holds the active pharmaceuticalagent for controlled release. In some situations it may be necessary toweld more of the internal layer based on the composition of the GRDF.

Gastric Retention Under Low and Medium Calorie Diet

The gastroretentive drug formulations maintain their physical integrityover a prolonged period of time, such that DMF is retained in thestomach for up to 24 hours under low or medium calorie diet. The use ofa low and medium calorie diet is advantageous because it follows normaldietary habits of the patients and does not demand an excessive mealwith each instance of dosing of the GRDF. Although the GRDF may beretained in the stomach for extended periods of time all of the GRDFcomponents are degradable and undergo complete degradation once theyreach the intestine.

In a third embodiment, the folded gastroretentive dosage form of thepresent invention comprises an internal layer comprising DMF and atleast one outer membrane covering the internal layer, wherein the outermembrane is hydratable at a rate greater than that of the internallayer. The outer membrane and the internal layer are arranged in anaccordion folded configuration and the outer membrane and the internallayer provide sufficient mechanical force to unfold from the initialaccordion folded configuration to an unfolded configuration when exposedto gastric fluid.

In certain embodiments, the gastrorentive dosage form is retained in thestomach for at least 3 hours, at least 4 hours, at least 8 hours, or atleast 12 hours.

In a first specific embodiment, the folded gastroretentive dosage formis a delayed pulse release form, which does not substantially releaseDMF when the device is retained in the stomach; while provides immediaterelease of DMF in small intestine. In one embodiment, less than 20%,less than 10%, less than 5% or less than 1% of DMF is released isreleased in the stomach. In one embodiment, more than 70%, more than80%, more than 90%, more than 95% or more than 99% of DMF is releasedwithin 2 hours or within 1 hour in small intestine.

In one embodiment, in the delayed pulse release form described above,the internal layer comprises DMF coated particles of the presentinvention.

In another embodiment, in the delayed pulse release form describedabove, the internal layer comprises non-enterically coated DMF. In oneembodiment, the non-enterically coated DMF is embedded into an entericlayer. Alternatively, the dosage form further comprises two entericlayers sandwiching the internal layer therebetween, wherein the entericlayer comprises one or more enteric polymers described herein. Inanother embodiment, the non-enterically coated DMF is embedded into theinternal layer comprising one or more enteric polymers. Any entericpolymers known in the art, particularly those described herein can beused in the dosage forms described herein.

In one embodiment, the internal layer comprises the DMF coated particlesof the present invention (e.g., those described in the second aspect andany specific embodiments described therein) and a polymer substantiallyuniformly distributed throughout the internal layer. The polymer can beany suitable polymer or polymer combinations that are insoluble ingastric medium.

In a second specific embodiment, the folded gastroretentive dosage formis a delayed sustained release form. The internal layer comprises DMFcoated particles of the present invention and releases DMF coatedparticles in the stomach over an extended period of time. In oneembodiment, 70-100%, 80-100%%, or 90-100% of DMF coated particles arereleased from the internal layer over 4-20 hours, over 8-20 hours, over8-12 hours or over 4-8 hours.

The internal layer comprises the DMF coated particles of the presentinvention (e.g., those described in the second aspect and any specificembodiments described therein) and a polymer substantially uniformlydistributed throughout the internal layer. The polymer can be adegradable hydrophilic polymer which is not instantly soluble in gastricfluid, a degradable enteric polymer which is substantially insoluble atpH less than 5.5, a hydrophobic polymer or mixtures thereof. It canfurther comprise acceptable pharmaceutical additives, such asplasticizers, humectants, fillers and others.

Examples of degradable hydrophilic polymers which are not instantlysoluble in gastric fluid suitable for the invention are hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone,polyethylene oxide and methylcellulose. Preferably, the enteric polymeris a polymethacrylate copolymers, cellulose acetate phthalate,hypromelose acetate succinate or hypromellose phthalate. These polymersare combined with the DMF coated particles of the present invention(e.g., those described in the second aspect and any specific embodimentsdescribed therein).

In certain embodiments, the internal layer described above (e.g. in thethird embodiment or the first or second specific embodiment) has planaraccordion geometry. This feature, together with the presence of polymersas described above in the internal layer provides the internal layerwith substantial mechanical strength. Preferably, the internal layer hasa mechanical strength with Young's modulus of from about 0.5 to 15Kgf/mm². Preferably, the range could be from about 3.0 to about 10.0Kgf/mm² or from about 3.0 to about 6.0 Kg f/mm². The stress may rangefrom about 0.03 to about 0.6 Kgf/mm² after 1 hour in simulated gastricfluid, such that the gastroretentive drug formulation reaches itsmaximum strength within one hour in simulated gastric fluid.Alternatively the range for stress may be from about 0.05 to about 0.4Kgf/mm² or about 0.1 to about 0.4 Kgf/mm².

In certain embodiments, the outer membranes in the device describedabove swell in the presence of gastric fluid and are fully degradablewithin two hours in simulated intestinal fluid. The combination ofswelling outer membrane layers with a non-swelling internal layer havingplanar accordion geometry causes the internal layer to undergo anunfolding process once the formulation reaches the stomach, thusextending gastric residence time and preventing the drug-containingdosage form from being evacuated until complete release. In oneembodiment the internal layer has a swelling rate less than the swellingrate of the membrane.

Each of the outer membranes in the gastroretentive drug formulationscomprises at least one polymeric combination of a hydrophilic polymerand a polymer, insoluble in gastric media, and at least one plasticizer.

Examples of suitable ingredients for the invention include gelatin,hydroxypropylcellulose, hydroxypopyl methycellulose, pectin,polyethylene oxide, starch, and zein. Preferably, the hydrophilicpolymer is gelatin. The amount of gelatin in each of the outer membranesis between about 20 and about 45% of the total outer membranecomposition, and preferably between about 25 and about 35% of the totalouter membrane composition.

Examples of enteric polymers that can be used in the outer membranesinclude hypromellose phthalate, hypromellose acetate succinate andpolymethacrylate co-polymers. Preferably, the enteric polymer ispolymethacrylate copolymer type A or polymethacrylate copolymer type C.

Plasticizers suitable for the invention include various polyethyleneglycols, glycerin, triethylcitrate. Preferably, the plasticizer ispropylene glycol.

In certain embodiments, the outer membrane permits passage of gastricmedia from the environment to the internal layer and permits passage ofthe active agent from the internal layer through the membrane to theenvironment.

In certain embodiments, the folded gastroretentive dosage form describedin the third embodiment or the first or second specific embodimentcomprises two outer membranes sandwiching the internal layerstherebetween. When the dosage form further comprises two enteric layersas described above, the two outer membranes are located outside of thetwo enteric layers respectively.

In certain embodiments, the folded gastroretentive dosage form describedabove is placed in a capsule for oral intake, wherein the capsule isdissolvable in the stomach.

In certain embodiments, when exposed to gastric medium, the dosage formunfold from the initial accordion folded configuration to an unfoldedconfiguration having a length of at least 20 mm within 30 minutes,within 20 minutes, within 15 minutes or within 10 minutes.

In certain embodiments, the gastroretentive drug formulationseffectively unfold and retain their mechanical integrity in acidic pHfor up to 24 hours and completely biodegrade after 3 hours in simulatedintestinal fluid.

d. Intestinal Retention Dosage Form

In some embodiments, the invention provides an intestinal retentiondosage form for delivering an API to a subject treated. In someembodiments, the intestinal retention dosage form releases the API inthe GI tract of a subject in a sustained period of time between about0.25 and about 24 hours (e.g., about 2, about 4, about 6, about 8, about10, about 12, about 14, about 16, about 18, about 20, about 22, or about24 hours). Various methods for achieving intestinal retention are known,for example, via mucoadhesion or mechanical retention.

Mucoadhesive Dosage Form

In some embodiments, the intestinal retention dosage form is amucoadhesive dosage form, which is adhesive to mucosal surface of thegastrointestinal tract (e.g., small intestine) of a subject treated. Insome embodiments, the API (e.g., the DMF coated particles described inthe second aspect or any embodiments described therein) in themucoadhesive dosage form is retained in the small intestine of a subjecttreated. Various techniques for preparing a mucoadhesive dosage form areknown. For example, U.S. Pat. No. 6,022,562, incorporated by referenceherein, discloses microcapsules containing particles of drug that arecoated with a film-forming polymer derivative, a hydrophobicplasticizer, a functional agent, and a nitrogen-containing polymer.These microparticles remain in the small intestine and release the drugover a period of time. Methods for evaluating effectiveness ofmucoadhesive dosage forms are also known.

U.S. Publication No. 2004/0234601 A1, incorporated by reference herein,also discloses a mucoadhesive dosage form.

Another example of a mucoadhesive dosage form is disclosed in U.S. Pat.No. 8,298,574 B2, incorporated by reference herein.

Mucoadhesive dosage forms herein can comprise an API and one or moremucoadhesive polymers. In some embodiments, the API is seal coated,enterically coated, or seal and enterically coated. In some embodiments,the only active pharmaceutical ingredient in the mucoadhesive dosageform is DMF. Suitable mucoadhesive polymers are known and include anypolymer that is or becomes adhesive to a mucosal membrane (e.g., mucosalmembrane of small intestine) upon hydration. The mucoadhesive polymerscan be cationic, anionic, or neutral. The mucoadhesive polymers can benatural or synthetic. The mucoadhesive polymer can be biocompatible. Themucoadhesive polymer can be water soluble or water insoluble.

Non-limiting synthetic mucoadhesive polymers suitable for the inventioninclude, for example, poly(acrylic acid), polyvinyl alcohol, polyamides,hydroxypropyl methylcellulose (HPMC), poly(methylacrylate) derivatives,polycarbonates, polyalkylene glycols, polyvinyl ethers/esters/halides,methylcellulose (MC), sodium carboxymethylcellulose (CMC),polymethylmethacrylic acid, and hydroxypropyl cellulose (HPC).

Non-limiting biocompatible mucoadhesive polymers suitable for theinvention also include, for example, cellulose based polymers, ethyleneglycol polymers and its copolymers, oxyethylene polymers, polyvinylalcohol, polyvinyl acetate, and esters of hyaluronic acid.

Non-limiting synthetic mucoadhesive polymers suitable for the inventionalso include, for example, cellulose derivatives (e.g., CMC, sodium CMC,thiolated CMC, hydroxylethyl cellulose (HEC), HPC, HPMC, methylcellulose (MC), methylhydroxyethylcellulose) and poly(acrylicacid)-based polymers (e.g., polyacrylic acid (PAA), polyacrylates,poly(methylvinylether-comethacrylic acid), poly(2-hydroxyethylmethacrylate), poly(acrylic acid-co-ethylhexylacrylate),poly(methacrylate), poly(alkylcyanoacrylate),poly(isohexylcyanoacrylate), poly(isobutylcyanoacrylate), or copolymerof acrylic acid and PEG).

Non-limiting natural mucoadhesive polymers suitable for the inventioninclude, for example, agarose, chitosan, gelatin, pectin, sodiumalginate, and various gums (e.g., guar, xanthan, gellan, carrageenan).

Non-limiting cationic mucoadhesive polymers suitable for the inventioninclude, for example, aminodextran, chitosan, trimethylated chitosan,and dimethylaminoethyl dextran.

Non-limiting anionic mucoadhesive polymers suitable for the inventioninclude, for example, Chitosan-EDTA, Cellulose Propionate (CP), CMC,pectin, PAA, polycarbonate (PC), sodium alginate, sodium CMC, andxanthan gum.

Non-limiting neutral mucoadhesive polymers suitable for the inventioninclude, for example, hydroxyethyl starch, HPC, poly(ethylene oxide),Poly(Vinyl Acetate) (PVA), poly(vinyl pyrrolidone) (PVP), andscleroglucan.

Non-limiting water soluble mucoadhesive polymers suitable for theinvention include, for example, CP, hydroxylethylcellulose (HEC), HPC,HPMC, PAA, sodium CMC, and sodium alginate.

Non-limiting water insoluble mucoadhesive polymers suitable for theinvention include, for example, chitosan, ethyl cellulose (EC), and PC.

In some embodiments, the one or more mucoadhesive polymers compriseschitosan, lectin, or a combination thereof. In some embodiments, the oneor more mucoadhesive polymer can be any combination of the suitablemucoadhesive polymers described above.

In any of the embodiments described herein, the mucoadhesive dosage formmay be in any suitable forms (e.g., microspheres, microparticles,nanoparticles, films, or tablets). In some embodiments, the mucoadhesivedosage form is in the form of microspheres. In some embodiments, themucoadhesive dosage form is in the form of tablets.

In some embodiments, the mucoadhesive dosage form releases the API(e.g., DMF) in the GI tract of a subject in a sustained period of time(e.g., about 2, about 4, about 6, about 8, about 10, about 12, about 14,about 16, about 18, about 20, about 22, or about 24 hours).

Mechanical Retention

In some embodiments, the intestinal retention dosage form is a dosageform comprising a plurality of API containing microparticles having amean diameter of about 50 microns to about 1000 microns (e.g., about 50,100, 150, 200, 300, 400, 500, 750, 1,000 microns, or any ranges thereof)that are retained (e.g., mechanically retained) in the GI tract (e.g.,small intestine) for an extended period of time from about 2 hours toabout 12 hours (e.g., about 2, 3, 4, 5, 6, 7, 8, 10, 12, or any rangesthereof). In some embodiments, the API in the intestinal retentiondosage form is retained in the small intestine of a subject treated. Insome embodiments, the microparticles have a mean diameter of about 100microns to about 500 microns. In some embodiments, the microparticleshave a mean diameter of about 50 microns to about 500 microns. In someembodiments, the only active pharmaceutical ingredient in the intestinalretention dosage form is DMF. Methods for preparing a mechanicallyretained intestinal retention dosage form are known, for example, viathe Micropump® method.

B. Unit Dosage Forms

In a fourth aspect, the present invention provides unit dosage formscomprising the DMF coated particles described above in the second aspectof invention or any embodiments described therein. In certainembodiments, the unit dosage forms of the present invention have similarpharmacokinetic profile as the current twice a day dosing regimen andare suitable for once a day dosing.

The controlled release dosage form described in the third aspect of thepresent invention may be provided as a unit dosage form or part of aunit dosage form or in a kit.

In some embodiments, a kit (e.g., a blister pack) comprises one or morepharmaceutical formulations, wherein the pharmaceutical formulation whenorally dosed to a subject delivers to the GI tract (e.g., upper GI tractor lower GI tract) of the subject treated, the total daily dose of API,in a sustained or pulsatile manner (e.g., to the upper gastrointestinaltract or lower GI tract (e.g., small intestine) of a subject treated).In some embodiments, the kit (e.g., a blister pack) comprises at leasttwo physically separated dosage forms (e.g., two capsules, two tablets,or one capsule and one tablet), wherein at least one of the dosage formsis a controlled release dosage form described herein. In someembodiments, the only active ingredient in the pharmaceuticalformulation(s) of the kit (e.g., a blister pack) is DMF.

In some embodiments, the invention provides a unit dosage form. In someembodiments, the unit dosage form is a single unit of a controlledrelease dosage form described herein. In some embodiments, the unitdosage form is a combination of one or more units of a controlledrelease dosage form described herein and one or more units of a seconddosage form (e.g., a controlled release dosage form described herein, anenterically coated immediate release dosage form, a combinationthereof). In some embodiments, the controlled release dosage form is asustained release dosage form. In some embodiments, the second dosageform is a delayed release dosage form.

In some embodiments, the unit dosage form, when orally dosed to asubject, delivers to the GI tract (e.g., upper GI tract or lower GItract (e.g., small intestine)) of the subject treated, more than onedose of the API, in a sustained or pulsatile manner, wherein the unitdosage form comprises

a first dosage component comprising a first dose of the API; and

a second dosage component comprising a second dose of the API.

In some embodiments, the second dose of the API in the unit dosage formis retained in the stomach and/or small intestine of a subject treatedfor at least 3 hours (e.g., about 3 hours, about 4 hours, about 5 hours,about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours,about 15 hours, about 16 hours, about 17 hours, or any ranges thereof).In some embodiments, the second dose of the API in the unit dosage formis retained in the stomach and/or small intestine for about 3 hours toabout 17 hours. In some embodiments, the second dose of the API in theunit dosage form is retained in the stomach and/or small intestine of asubject treated for at least 4 hours, at least 5 hours, at least 6hours, at least 7 hours, or at least 8 hours. In some embodiments, thesecond dose of the API in the unit dosage form is retained in thestomach and/or small intestine of a subject treated for at least 5hours, at least 6 hours, or at least 7 hours.

In some embodiments, the second dosage component of the unit dosage formis a controlled release dosage form described above (e.g.,gastroretentive folded dosage forms described in the third aspect of thepresent invention).

In some embodiments, the first and second dosage components may be inone dosage form (e.g., a tablet or a capsule). In some embodiments, theonly active ingredients in the unit dosage form is DMF.

In some embodiments, the unit dosage form (e.g., as described herein)releases MMF, or a compound that can be metabolized into MMF in vivo, ina bimodal or multi-modal manner in which a first dose of the API afteran initial delay time to provide a pulse of drug release and one or moreadditional doses of the API are released each after a respective lagtime to provide additional pulses of drug release. In some embodiments,the pulses of drug release are delivered to the upper gastrointestinaltract of a subject treated. In some embodiments, the pulses of drugrelease are delivered to the lower gastrointestinal tract of a subjecttreated. In some embodiments, one pulse of drug release is delivered tothe upper gastrointestinal tract of a subject treated and a second pulseof drug release is delivered to the lower gastrointestinal tract of thesubject treated.

It may be advantageous to deliver DMF in pulses to the upper GI tractrather than to the lower GI tract for absorption. In some embodiments,the pulses of DMF are delivered to the upper gastrointestinal tract of asubject treated.

In some embodiments, the invention provides a unit dosage form thatdelivers MMF, or a compound that can be metabolized into MMF in vivo, inpulses to the upper GI tract upon oral administration of the unit dosageform. In some embodiments, the unit dosage form comprises

a first dosage component comprising a first dose of API; and

a second dosage component comprising a second dose of API;

wherein when the unit dosage form is administered to a subject orally,the first and second doses of API, are delivered to the upper GI tractof the subject in a pulsatile manner.

In some embodiments, the second dosage component of the unit dosage formis a controlled release dosage form described above in the third aspectof the invention.

In some embodiments, patients orally administered a unit dosage formdescribed herein (with or without food) once daily exhibit one or moreof the following pharmacokinetic parameters in the subject: (a) a meanplasma MMF AUC_(overall) ranging from about 4.81 h·mg/L to about 11.2h·mg/L; (b a mean plasma MMF AUC₀₋₁₂ ranging from about 2.4 h·mg/L toabout 5.5 h·mg/L; and (c) a mean AUC_(0-infinity) ranging from about 2.4h·mg/L to about 5.6 h·mg/L. In some embodiments, the subject treatedexhibits a pharmacokinetic profile characterized by both (a) and (b),both (a) and (c), or both (b) and (c). In some embodiments, the subjecttreated exhibits a pharmacokinetic profile characterized by (a), (b),and (c).

In some embodiments, a subject orally administered a unit dosage formdescribed herein once daily exhibits a mean MMF plasma area under thecurve 0-12 (AUC₀₋₁₂) of about 2.36 h·mg/L to about 5.50 h·mg/L, fromabout 2.75 h·mg/L to about 5.10 h·mg/L, or from about 3.14 h·mg/L toabout 4.91 h·mg/L. In one embodiment, the subject exhibits a meanAUC₀₋₁₂ of about 3.93 h·mg/L.

In some embodiments, a subject orally administered a unit dosage formdescribed herein (with or without food) once daily exhibits a mean MMFplasma overall area under the curve (AUC_(overall)) of about 4.81h·mg/mL to about 11.2 h·mg/mL, or from about 6.40 h·mg/L to about 10.1h·mg/L. In one embodiment, the subject exhibits a mean AUC_(overall) ofabout 8.02 h·mg/L.

First Dosage Component

Upon oral administration of the unit dosage form to a subject, the firstdosage component comprising a first dose of API, may provide the firstdose, for example, as a first pulse of an API, for absorption in theupper GI tract of the subject. In any of the embodiments describedherein, the first dosage component can be an enterically coatedimmediate release or a delayed release dosage form. In some embodiments,the only active ingredient in the first dosage component is DMF. In someembodiments, the first dosage component comprises the DMF coatedparticles of the present invention as described in the second aspect orany specific embodiments described therein.

In some embodiments, suitable amounts of API for the first dosagecomponent include those that can provide, by itself or in combinationwith one or more doses from, for example, a second dosage component, adaily amount of the respective compound ranging from about 1 mg/kg toabout 50 mg/kg (e.g., from about 2.5 mg/kg to about 20 mg/kg or fromabout 2.5 mg/kg to about 15 mg/kg).

Suitable doses of DMF for the first dosage component may be anytherapeutically effective dose, e.g., an amount that is effective intreating multiple sclerosis. For example, suitable doses of DMF for thefirst dosage component may be any dose from 20 mg to 1 g of DMF. In someembodiments, the suitable doses of DMF in the first dosage component maybe any dose from about 80 mg to about 1000 mg of DMF. In someembodiments, the suitable doses of DMF in the first dosage component maybe any dose from about 100 mg to about 750 mg of DMF. In someembodiments, the suitable doses of DMF in the first dosage component isabout 200 to about 600 mg. In some embodiments, the suitable doses ofDMF in the first dosage component may be any dose from about 300 toabout 600 mg.

In some embodiments, the DMF in the first dosage component is about 60mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg,about 240 mg, about 320 mg, about 360 mg, about 400 mg, about 480 mg,about 600 mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg ofDMF, or any ranges thereof.

The first dosage component can contain an amount of a compound that thatcan metabolize into MMF that provides an equivalent amount of MMF as thedoses of DMF described above.

Suitable first dosage component may be in a form of a micro-pellet, amicro-tablet, a capsule (such as a soft or hard gelatine capsule), agranulate, or a tablet. In some embodiments, the first dosage componentis in the form of microtablets or micropellets (e.g., enteric-coatedmicrotablets or micropellets). Suitable microtablets or micropelletsare, without limitation, those having a mean diameter of 5,000 micronsor less (e.g., 4,000 microns or less, 3,000 microns or less, 2,000microns or less, 1,000 microns or less, or 500 microns or less)exclusive of any optional coating applied to the microtablets ormicropellets. Methods for preparing microtablets or micropellets (e.g.,enteric-coated microtablets or micropellets) comprising DMF are known inthe art, for example, as described in U.S. Pat. No. 6,509,376 andincorporated by reference in its entirety herein.

In some embodiments, the first dosage component comprises an acidsoluble outer coating. For example, in some embodiments, the firstdosage component is in the form of enteric-coated microtablets ormicropellets, and the enteric-coated microtablets or micropellets areencapsulated with an acid soluble coating, e.g., in a soft-shell orhard-shell gelatin capsule.

Other suitable acid soluble coatings for the first dosage component areknown in the art and include those coatings that dissolve at a pH lessthan 6.0. Non-limiting examples of acid soluble coatings includegelatin, Eudragit® E-100, polyvinyl acetyl diethylaminoacetate, andchitosan coatings. The acid-soluble coating may be applied using varioustechniques (e.g., spray techniques) known to one skilled in the art.

The first dosage component may also comprise one or morepharmaceutically acceptable excipients in addition to those describedabove. Suitable pharmaceutically acceptable excipients are those knownin the art, for example, binders, fillers, disintegrants, glidants,lubricants, diluents, plasticizers, etc. as described in Remington'sPharmaceutical Science, 18^(th) Edition, 1990, Mack Publishing Company,Easton, Pa. (“Remington's”).

Second Dosage Component

The second dosage component is a controlled release dosage formdescribed above in the third aspect or any embodiments described therein(e.g. the gastroretentive folded dosage forms described in the thirdaspect of the invention). In some embodiments, the only activeingredient in the second dosage form is DMF.

In some embodiments, suitable amounts of API for the second dosagecomponent include those that can provide, by itself or in combinationwith one or more doses from, for example, a first dosage component, adaily amount of the respective compound (e.g., DMF) ranging from about 1mg/kg to about 50 mg/kg (e.g., from about 2.5 mg/kg to about 20 mg/kg orfrom about 2.5 mg/kg to about 15 mg/kg).

Suitable doses of DMF for the second dosage component may be anytherapeutically effective dose, e.g., an amount that is effective intreating multiple sclerosis. For example, suitable doses of DMF for thesecond dosage component may be any dose from 20 mg to 1 g of DMF. Insome embodiments, the suitable doses of DMF in the second dosagecomponent may be any dose from about 80 mg to about 1000 mg of DMF. Insome embodiments, the suitable doses of DMF in the second dosagecomponent may be any dose from about 100 mg to about 750 mg of DMF. Insome embodiments, the suitable doses of DMF in the second dosagecomponent is about 200 to about 600 mg. In some embodiments, thesuitable doses of DMF in the second dosage component may be any dosefrom about 300 to about 600 mg.

In some embodiments, the DMF in the second dosage component is about 60mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg,about 240 mg, about 320 mg, about 360 mg, about 400 mg, about 480 mg,about 600 mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg ofDMF, or any ranges thereof.

The second dosage component can contain an amount of a compound thatthat can metabolize into MMF that provides an equivalent amount of MMFas the doses of DMF described above.

In some embodiments, the second dosage component comprises an acidsoluble outer coating as described for the first dosage component.

Relationship of First and Second Dosage Components

In some embodiments, the first dosage component and the second dosagecomponent are both part of a capsule. In some embodiments, the seconddosage component is a floating capsule comprising an acid soluble cap(e.g., gelatin cap), and the first dosage component is placed between apulsatile coating or layer of the second dosage component and the acidsoluble cap (e.g., gelatin cap). Upon oral administration, the acidsoluble cap (e.g., gelatin cap) is dissolved in the gastric fluid andreleases the first dose of drug (e.g., DMF) from the first dosagecomponent. At the same time, the second dosage component floats in thegastric fluid and is slowly eroded by the gastric fluid until apulsatile coating or layer is disintegrated and releases the second doseof drug (e.g., DMF).

In some embodiments, the first dosage component encapsulates the seconddosage component. In some embodiments, the first dosage component isfurther encapsulated by an acid soluble coating. In some embodiments,the second dosage component comprises an outer acid resistant coating.

In some embodiments, the first dosage component and the second dosagecomponents are not physically attached to each other (e.g., as twocapsules, two tablets, or one capsule and one tablet), which areprovided (e.g., packaged) in a kit (e.g., a blister pack). For example,in some embodiments, the first dosage component is anon-gastro-retentive capsule (e.g., containing 120 mg or 240 mg DMF) andthe second dosage component is a controlled release dosage form (e.g.,as described herein). Thus, oral administration of the unit dosage formrequires orally administering a non-gastro-retentive capsule (e.g.,containing 120 mg or 240 mg DMF) and one controlled release dosage form(e.g., as described herein) at the same or substantially the same timeas a single dose.

In another embodiment, the unit dosage form is a gastroretentive foldeddosage form comprising an immediate-release component and a controlledrelease component. These dosage forms comprise an internal layer orcompartment and at least two outer membranes as described above in thesecond embodiment of the third aspect of the present invention, andadditionally comprise one or more immediate release layers covering theouter membranes and comprising DMF (e.g., DMF coated particles describedin the second aspect invention or any embodiments described therein) anda soluble polymer that provides for the immediate release of DMF.Examples of soluble polymers that can be used in the immediate releasewhich can be selected from soluble cellulose derivatives, i.e. methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose;various grades of povidone; polyvinyl alcohol and its derivatives, i.e.Kollicoat IR; soluble gums and others. The films may further comprisesurface-active agents, plasticizers and humectants, such as PEGs,different grades of polysorbates and sodium lauryl sulfate, for example.

In another embodiment, the unit dosage form are for the immediaterelease and the sustained release of DMF in the gastrointestinal tractand comprise: i.) an internal layer or compartment comprising the DMFcoated particles of the present invention (e.g., those described in thesecond embodiment or any specific embodiments described above) and apolymer; ii.) two membranes forming together an envelope around theinner membrane, each comprising at least one polymeric combination of apolymer which is not soluble in gastric juice, and a hydrophilicswelling polymer, and at least one plasticizer; and iii.) one or twolayers comprising DMF (e.g., the DMF coated particles described in thesecond embodiment or any specific embodiments described therein) and asoluble polymer that provides for the immediate release of DMF and isattached to the outside of one outer membrane or both outer membranes orpart of an outer membrane. Optionally an additional layer may becovering each immediate release membrane comprising a powder or a filmthat prevents adherence of the outer membrane or IR membrane onto itselfwhen folded inside the capsule. In some embodiments, theimmediate-release membranes possess surface properties that preventadherence onto itself when folded inside the capsule.

While the internal layer and outer layer are generally welded together,the immediate release layer will not generally require such a strongconnection with the rest of the GRDF device. Rather the immediaterelease formulation will quickly dissolve in order to deliver the drugof interest. The immediate release layer may be affixed to the outsideof the GRDF using a compatible solvent, ultrasonic welding, or othermeans.

The ability to add an additional immediate release layer is particularlyhelpful in the development of once a day dosage forms. By combining theimmediate and controlled release nature of the current invention, onecan alter DMF release profile. Consequently, patients may receive bothan immediate bolus of DMF as well as a prolonged delivery of DMF withthe purpose of establishing therapeutic levels of the drug quickly andmaintaining these levels for prolonged period of time, up to 24 hour.

Coating

As an additional method of delivering the immediate release of the drug,a coating may be applied to the capsule comprising the drug. Upon entryinto the stomach, the coating will immediately allow release of the drugand enhance the release profile of the drug. Methods for applyingcoating to a capsule are well known to those of skill in the art.

In one embodiment, the unit dosage form of the present inventioncomprises:

a first dosage component comprising a first dose of DMF, wherein thefirst dosage component is an enterically coated immediate release dosageform; and

a second dosage component comprising a second dose of DMF, wherein thesecond dose of DMF in the unit dosage form is retained in the stomach asubject treated for at least 3 hours, wherein the second dosagecomponent is any gastroretentive folded dosage forms described in thethird aspect of the invention.

In one embodiment, the gastrorententive folded dosage form is asdescribed in the third embodiment described above. More specifically,the gastrorentative folded form is a delayed pulse release dosage formdescribed in the first specific embodiment above. In another morespecific embodiment, the gastrorentative folded form is a delayedsustained release dosage form described in the second specificembodiment above.

In certain embodiments, the first dosage component and the second dosagecomponent are not physically attached to each other (e.g., as twocapsules, two tablets, or one capsule and one tablet), which areprovided (e.g., packaged) in a kit (e.g., a blister pack).

Unit Dosage Form Comprising More than Two Dosage Components

In some embodiments, the unit dosage form is configured to have morethan two dosage components, e.g., to provide a sustained release, ormore than two pulses of releases of the API. In some embodiments, theunit dosage form comprising the first and second dosage componentsfurther comprises one or more dosage components comprising one or moredoses of the API, wherein upon oral administration of the unit dosageform to a subject, the first, second, and the one or more doses of theAPI, are delivered to GI tract (e.g., upper GI tract or lower GI tract)of the subject in a sustained or pulsatile manner. The time between twoconsecutive pulses (e.g., between the first and second pulse, or thesecond and third pulses, etc.) in a pulsatile delivery system may be thesame or different, each may be about 2 hours, about 4 hours, about 6hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, orany ranges thereof.

4. Method of Treatment

DMF and its active metabolite MMF have been indicated as useful for thetreatment or prophylactic treatment of various diseases or disorders.Thus, in some embodiments, the invention also provides a method oftreatment of diseases or disorders where administering DMF is helpful,the method comprising orally administering to a subject in need thereofa unit dosage form (e.g., as described herein) once per day (i.e., QDdosing). In some embodiments, the invention also provides a method oftreatment or prophylactic treatment of diseases or disorders whereadministering DMF is helpful, the method comprising orally administeringto a subject in need thereof a pharmaceutical composition comprising DMFparticles described in the first aspect of the invention or DMF coatedparticles described in the second aspect of the invention. Thepharmaceutical composition of the present invention comprises the DMFparticles or the DMF coated particles of the present invention and apharmaceutically acceptable carrier or excipient.

The treatment may be acute or chronic (e.g., more than 1, 2, 3, 4, 5, 8,10, or 12 weeks) treatments.

In some embodiments, the disease or disorder where administering DMF ishelpful is:

an autoimmune disease selected from the group consisting ofpolyarthritis, rheumatoid arthritis, multiple sclerosis,graft-versus-host reactions, juvenile-onset diabetes, Hashimoto'sthyroiditis, Grave's disease, systemic Lupus erythematodes (SLE),Sjogren's syndrome, pernicious anaemia and chronic active (=lupoid)hepatitis, psoriasis, psoriatic arthritis, neurodermatitis and enteritisregionalis Crohn;

a mitochondrial disease selected from the group consisting of Parkinsonsyndrome, Alzheimer's disease, Chorea Huntington disease, retinopathiapigmentosa or forms of mitochondrial encephalomyopathy;

a NF-kappaB mediated diseases selected from the group consisting ofprogressive systemic sclerodermia, osteochondritis syphilitica(Wegener's disease), cutis marmorata (livedo reticularis), Behcetdisease, panarteriitis, colitis ulcerosa, vasculitis, osteoarthritis,gout, artenosclerosis, Reiter's disease, pulmonary granulomatosis, typesof encephalitis, endotoxic shock (septic-toxic shock), sepsis,pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (acutehepatitis, chronic hepatitis, toxic hepatitis, alcohol-inducedhepatitis, viral hepatitis, jaundice, liver insufficiency andcytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangialnephritis, post-angioplastic restenosis, reperfusion syndrome,cytomegaloviral retinopathy, adenoviral diseases such as adenoviralcolds, adenoviral pharyngoconjunctival fever and adenoviral ophthalmia,AIDS, Guillain-Barre syndrome, post-herpetic or post-zoster neuralgia,inflammatory demyelinising polyneuropathy, mononeuropathia multiplex,mucoviscidosis, Bechterew's disease, Barett oesophagus, EBV(Epstein-Barr virus) infection, cardiac remodeling, interstitialcystitis, diabetes mellitus type II, human tumour radiosensitisation,multi-resistance of malignant cells to chemotherapeutic agents(multidrug resistance in chemotherapy), granuloma annulare and cancerssuch as mamma carcinoma, colon carcinoma, melanoma, primary liver cellcarcinoma, adenocarcinoma, kaposi's sarcoma, prostate carcinoma,leukaemia such as acute myeloid leukaemia, multiple myeloma(plasmocytoma), Burkitt lymphoma and Castleman tumour;

a cardiovascular disease selected from the group consisting of cardiacinsufficiency, myocardial infarct, angina pectoris and combinationsthereof;

a respiratory disease selected from the group consisting of asthma,chronic obstructive pulmonary diseases, PDGF induced thymidine uptake ofbronchial smooth muscle cells, bronchial smooth muscle cellproliferation, and combinations thereof;

a neurodegeneration or neuroinflammation selected from the groupconsisting of Adrenal Leukodystrophy (ALD), Alcoholism, Alexander'sdisease, Alper's disease, Alzheimer's disease, Amyotrophic lateralsclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten disease(also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovinespongiform encephalopathy (BSE), Canavan disease, Cerebral palsy,Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease,Familial Fatal Insomnia, Frontotemporal lobar degeneration, Huntington'sdisease, HIV-associated dementia, Kennedy's disease, Krabbe's disease,Lewy body dementia, Neuroborreliosis, Machado-Joseph disease(Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiplesclerosis, Narcolepsy, Niemann Pick disease, Parkinson's disease,Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis,Prion diseases, Progressive Supranuclear Palsy, Refsum's disease,Sandhoff disease, Schilder's disease, Subacute combined degeneration ofspinal cord secondary to Pernicious Anaemia,Spielmeyer-Vogt-Sjögren-Batten disease (also known as Batten disease),Spinocerebellar ataxia, Spinal muscular atrophy,Steele-Richardson-Olszewski disease, Tabes dorsalis, Toxicencephalopathy, LHON (Leber's Hereditary optic neuropathy), MELAS(Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke), MERRF(Myoclonic Epilepsy; Ragged Red Fibers), PEO (Progressive ExternalOpthalmoplegia), Leigh's Syndrome, MNGIE (Myopathy and externalophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy),Kearns-Sayre Syndrome (KSS), NARP, Hereditary Spastic Paraparesis,Mitochondrial myopathy, and Friedreich Ataxia; or

a demyelinating neurological disorder selected from the group consistingof optic neuritis, acute inflammatory demyelinating polyneuropathy(AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), acutetransverse myelitis, progressive multifocal leucoencephalopathy (PML),acute disseminated encephalomyelitis (ADEM) or other hereditarydisorders (e.g., leukodystrophies, Leber's optic atrophy, andCharcot-Marie-Tooth disease).

In some embodiments, the disease or disorder where administering DMF ishelpful is a neutrophil mediated disease or disorder (e.g., an allergicdisease or disorder, an inflammatory disease or disorder, an autoimmunedisease or disorder, or a tumor).

Non-limiting examples of autoimmune diseases or disorders includeautoimmune Addison's disease, autoimmune hemolytic anemia, autoimmunehepatitis, autoimmune inner ear disease, autoimmune lymphoproliferativesyndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), orautoimmune skin blistering diseases (AIBD).

Non-limiting examples of autoimmune skin blistering diseases includeepidermolysis bullosa acquistita (EBA), pemphigoid disease (e.g.,bullous pemphigoid, mucous membrane pemphigoid, or pemphigoidgestationis), IgA-mediated bullous dermatoses (e.g., DermatitisHerpetiformis or Linear IgA Bullous Dermatosis), and pemphigus disease(e.g., IgA Pemphigus).

Non-limiting neutrophil mediated diseases or disorders also include aninflammatory skin or subcuteneous disease selected from the groupconsisting of Pyoderma Gangrenosum, Erosive Pustular Dermatosis of theScalp, Sweet's Syndrome, Bowel-associated Dermatosis-arthritis Syndrome,Pustular Psoriasis, Acute Generalized Exanthematous Pustulosis,Keratoderma Blenorrhagicum, Sneddon-Wilkinson Disease, AmicrobialPustulosis of the Folds, Infantile Acropustulosis, Transient NeonatalPustulosis, Neutrophilic Eccrine Hidradenitis, Rheumatoid NeutrophilicDermatitis, Neutrophilic Urticaria, Still's Disease, ErythemaMarginatum, Unclassified Periodic Fever Syndromes/AutoinflammatorySyndromes, Bullous Systemic Lupus Erythematosus, and NeutrophilicDermatosis of the Dorsal Hands (Pustular Vasculitis);

Non-limiting neutrophil mediated diseases or disorders also include:

an allergic condition selected from the group consisting of anaphylaxis,allergic rhinitis and allergic asthma;

neutrophil mediated respiratory disease selected from the groupconsisting of lung cancer, severe asphyxic episodes of asthma, acutelung injury, and Acute Respiratory Distress Syndrome;

an acute tissue injury selected from the group consisting of acutekidney injury, ischemia reperfusion injury, sepsis, and septicemia withmultiorgan failure;

an inflammatory bowel disease selected from the group consisting ofulcerative colitis, Crohn's disease, and inderteminate colitis; and

sickle cell crisis or acute chest syndrome.

In some embodiments, the disease or disorder where administering DMF ishelpful is a disease or disorder that is associated with aberrantPI3K/AKT signaling including cancer, chronic inflammation and allergy,neurodegerative disease, cardiovascular disease and metabolic diseases.Non-limiting examples of disease or disorders that are associated withaberrant PI3K/AKT signaling include all forms of cancer, precancerouslesions, cardiovascular disease, rheumatologic disease, pulmonarydisease, dermatologic disease, gynecological diseases, vascular disease,neurologic disease, and infectious disease including bacterial, viral,retroviral, and parasitic diseases. In some embodiments, the disease ordisorder to be treated is cancer. Non-limiting examples of cancerinclude breast cancer, lung cancer, ovarian cancer, uterine cancer,brain cancer, sarcoma, melanoma, leukemia, lymphoma, colorectal cancer,prostate cancer, and liver cancer. In some embodiments, the disease ordisorder to be treated is rheumatologic disease, e.g., rheumatoidarthritis or osteoarthritis. In some embodiments, the disease ordisorder to be treated is pulmonary disease, e.g., allergic rhinitis,chronic obstructive pulmonary disease (COPD).

In some embodiments, the disease or disorder where administering DMF ishelpful is a disease or disorder that is associated with aberrant p38MAPK signaling. Non-limiting examples of such diseases include COPD(including chronic bronchitis and emphysema), asthma, paediatric asthma,cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergicrhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis,allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis,inflamed joints secondary to rheumatoid arthritis or osteoarthritis,rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growthand metastasis of tumours including non-small cell lung carcinoma,breast carcinoma, gastric carcinoma, colorectal carcinomas and malignantmelanoma.

In some embodiments, the invention provides a method of treatingmultiple sclerosis (e.g., relapsing-remitting MS, secondary progressiveMS, primary progressive MS, progressive relapsing MS) in a subject inneed thereof, wherein the method comprises administering to the subjecta controlled release dosage form or an unit dosage form (e.g., asdescribed herein) once per day.

In some embodiments, the unit dosage form comprises

a first dosage component comprising a first dose of about 80 mg to about360 mg (e.g., about 120 mg or about 240 mg) of an API; and

a second dosage component comprising a second dose of about 80 mg toabout 720 mg (e.g., about 120 mg or about 240 mg) of the API;

wherein when the unit dosage form is administered to a subject orally,the first and second doses of the API are delivered to the upper GItract of the subject in a sustained or pulsatile manner.

In any of the embodiments described herein, the controlled releasedosage form or unit dosage form may be administered to a subject with orwithout food.

In some embodiments, the first and second dosage components of the unitdosage form are physically separated from each other (e.g., as twocapsules, two tablets, or one capsule and one tablet) and are providedin a kit (e.g., a blister pack). In some embodiments, the first andsecond dosage components of the unit dosage form are both part of onedosage form (e.g., a pill, a tablet, or a capsule).

In some embodiments, the only active ingredient in the controlledrelease dosage form or unit dosage form is DMF.

In some embodiments, the method comprises orally administering to thesubject the controlled release dosage form or unit dosage form with orwithout food once per day, wherein the subject exhibits one or more ofthe following pharmacokinetic parameters: (a) a mean plasma MMFAUC_(overall) ranging from about 4.81 h·mg/L to about 11.2 h·mg/L; (b) amean plasma MMF AUC₀₋₁₂ ranging from about 2.4 h·mg/L to about 5.5h·mg/L; and (c) a mean AUC_(0-infinity) ranging from about 2.4 h·mg/L toabout 5.6 h·mg/L. In some embodiments, the subject treated exhibits apharmacokinetic profile characterized by both (a) and (b), both (a) and(c), or both (b) and (c). In some embodiments, the subject treatedexhibits a pharmacokinetic profile characterized by (a), (b), and (c).

In some embodiments, the subject exhibits a mean MMF plasma area underthe curve 0-12 (AUC₀₋₁₂) of about 2.36 h·mg/L to about 5.50 h·mg/L, fromabout 2.75 h·mg/L to about 5.10 h·mg/L, or from about 3.14 h·mg/L toabout 4.91 h·mg/L. In some embodiments, the subject exhibits a meanAUC₀₋₁₂ of about 3.93 h·mg/L.

In some embodiments, the subject exhibits a mean MMF plasma overall areaunder the curve (AUC_(overall)) of about 4.81 h·mg/mL to about 11.2h·mg/mL, or from about 6.40 h·mg/L to about 10.1 h·mg/L. In someembodiments, the subject exhibits a mean AUC_(overall) of about 8.02h·mg/L.

EXAMPLES Example 1. General Description of Wet-Milling Process

50 kg Fumaric acid was added to the reactor followed by 229.3 kgmethanol and 10.6 kg sulfuric acid. The reactor contents was heated to62-65° C. (or reflux conditions) and held at that temperature for atleast 3 h to allow conversion of fumaric acid to dimethyl fumarateproduct. At the end of hold period the solution is recirculated througha Silverson™ high-shear mixer (HSM) operated at 3400-3600 RPM whilesimultaneously cooled to terminal temperature 10-15° C. in a 4-10 hcooling ramp. The dimethyl fumarate particles which were crystallizedout of solution initially (nucleation point) around 60-61° C. andthroughout the cooling period were exposed to the shear actions duringthe recirculation from the reactor through the Silverson HSM. The shearactions broke the large particles to smaller particles. The millingmaybe stopped when the particle size reaches the desired target. Thiscan be determined based on in-process measurements and/or milling timeor number of recirculation. After the milling completion, the slurrycontaining milled dimethyl fumarate was transferred to the filter orcentrifuge to isolate the solids, the isolated solids were washed with3-6×50 L methanol, and finally vacuum dried at 24-28° C. with nitrogenbleed until less than 1500 ppm residual methanol was achieved.

The dimethyl fumarate product obtained by the process and equipmentdescribed above has shown improved bulk powder properties relative tomaterial produced using jet mill (dry mill). The improved powderrheology property can be associated among other things by two keyfactors below:

-   -   a. Powder uniformity and the presence of less fines particles        with size less than 10 microns; Table 1 below show particle size        distribution which shows smaller span (a measure of particle        uniformity) for wet milled material compare to jet milled        material (dry mill).    -   b. The differences in permeability as measured by FT4 (Freeman        Technology) bulk powder testing. The powder permeability (see        Table 2) can be associated to its tendency towards bridging or        segregation which are highly undesired occurrences during the        manufacture of drug product. The permeability number measures        relative ease for air to travel through a conditioned powder        bed; low number indicates high permeability and therefore less        chances for bridging/segregation

TABLE 1 Particle Size of Dimethyl fumarate measured by Malvern LaserDiffraction. D × 10 D × 50 D × 90 D × 97 <10 μm (μm) (μm) (μm) (μm) SpanWet-Milled 2014-4281-A.4 2.61% 31.9 96 182 235 1.562 2014-4281-A.8 3.87%27.2 70.8 148 208 1.71 2014-4281-A.9 3.02% 26.8 88.2 166 210 1.58A14DS0977 1.87% 51.5 127 249 319 1.554 A14DS0978 2.32% 44.1 113 224 2941.593 AMDS1097 2.89% 33.1 87.8 189 257 1.772 Jet-Milled 11P1310 11.48% 930 70 97 2.05 * Batches 2014-4281-A.4, A.8 and A.9 are produced using aSilverson high-shear mixer. Batches A14DS0977, 0978 and 1097 areproduced using a IKA high-shear mixer.

TABLE 2 Dimethyl Fumarate Rheology Properties measured by FT4 Low StressFlow High Stress Specific Rate Permeability Permeability Flow EnergyIndex (1 kpa) (15 kpa) Function Wet-Milled 2014-4281-A.4 4.87 1.11 0.050.10 5.84 2014-4281-A.8 6.64 1.37 0.04 0.12 3.29 2014-4281-A.9 6.42 1.330.09 0.18 2.50 A14DS0978 8.67 1.68 0.15 0.17 12.84 AMDS1097 9.19 1.540.15 0.18 5.97 Jet-Milled B1417-140304 5.48 1.50 0.24 0.52 2.25

The improvement in powder flow for wet milled dimethyl fumarate has beenalso shown with drug product blends containing dimethyl fumarate andother excipients such as in the current FDA approved twice a dayformulation. See FIG. 1.

Example 2. DMF Wet Milling—Large Scale Run

350 kg Fumaric acid in approximate 2100 L methanol and 77 kg sulfuricacid are heated to 60-65° C. (reflux conditions) and held at thattemperature to convert the fumaric acid to dimethyl fumarate. After aperiod of hold time (at least 4 h) the product solution is polishedfiltered to the crystallizer. The hot product solution in thecrystallizer is then recirculated through a silverson UHS450 high-shearmixer (HSM) and back to the crystallizer. The HSM is equipped with achoice of mill head or stator. Two stators type may be used, such asslotted disintegrating (medium stator) or square-hole high shear stator(fine stator). After the recirculation is established, the solution iscooled to 5-10° C. to crystallize the product out of solution whilesimultaneously milled in the HSM. The particle size reduction induced bythe HSM is monitored by crystal chord length (CLD) measurements usingFBRM (focused-beam reflective measurement) technology with probepositioned in either/and both the recirculation line or in the vessel.The recirculation (milling) is discontinued when the target CLD isachieved such as when the median value of a mean-square weighted CLDdistribution is less than 100 μm. Subsequently, the milled DMF isisolated using a filter centrifuge and dried to yield the final product.

The results of powder characterization for two 350 kg batches obtainedwith two different mill head are summarized in table below:

TABLE 3 Run 1 Run 2 Mill Head/Stator Type Slotted- Square-Disintegrating hole high- shear Analysis by Laser Diffraction: d₁₀ 35 μm39 μm d₅₀ 83 μm 83 μm d₉₀ 156 μm  150 μm  Powder Characterization byFT4: Flow rate Index (FRI) 1.61 1.39 Specific Energy (mJ/g) 12.21 12.18Permeability at 1 kPa (mbar) 0.31 0.31 Permeability at 15 kPa (mbar)0.33 0.34 Flow Function (FF) 10.3 4.95

Example 3. DMF Powder Characterization

DMF powder characterization was conducted using the FT4 Powder Rheometer(Freeman Technology Ltd, Tewkesbury, UK) using the 25 mm vessel assemblywhich consists of 23.5 mm diameter blades, vented piston, a segmentedrotational shear cell accessory; and a 10 or 25 ml borosilicate vessel.All powders were pre-conditioned by the instrument's built-inconditioning step.

Powder testing can be generally classify into three testing category,such as: dynamic tests to determine flow rate index (FRI) and specificenergy (SE), permeability tests to measure air transmission through apowder bed, and shear test to determine flow function (FF) which is anindication of powder flow properties under stress. Below are furtherdescriptions of the tests.

Dynamic Testing

Dynamic testing used the 23.5 mm diameter blades and a 25 ml powdersample in the borosilicate test vessel. Powder was filled into thevessel. The blades were simultaneously rotated and moved axially intothe powder sample as the axial and rotational forces were measured andused to calculate the dynamic flowability parameters. Among dynamicparameters tested are Flow rate Index (FRI) and Specific Energy (SE).Their measurement techniques are described below:

Flow Rate Index (FRI):

The FRI is a measure of a powder's sensitivity to variable flow rate andit is obtained as the ratio of the total energy required to inducepowder flow at 10 mm/s and 100 mm/s blade tip speed. A larger deviationfrom 1 indicates greater sensitivity of a powder to variable flow rate.

Specific Energy (SE)

SE is a measure of the powder flow in low stress environment and isderived from the shear forces acting on the blades as they rotate upwardthrough the powder. The SE is recorded as the flow energy of the powdernormalized by its weight in mJ/g during the upward spiral movement ofthe blades. A lower SE is an indication of a less cohesive powder andbetter flow properties.

Permeability Testing

The permeability test measures the ease of air transmission through abulk powder which can be related to the powder's flowability. Thepermeability testing used a vented piston with an aeration base and a 10ml powder sample in the borosilicate test vessel. Powder was filled intothe vessel. The powder bed with a vented piston is exposed to varyingnormal stresses increased stepwise from 1 kPa to max 15 kPa. Thepressure drop across the powder bed was measured while air was flushedthrough the powder at a constant velocity of 2 mm/s. The pressure dropvalues recorded in mBar at the lowest, 1 kPa, and highest, 15 kPa, Alower pressure drop is indicative of higher permeability and usually,better flow properties.

Shear Testing

Shear testing measures powder shear properties which involves the stresslimit required to initiate a powder flow. The shear testing used asegmented rotational shear cell head and a 10 ml powder sample in theborosilicate test vessel. Powder was filled into the vessel. The shearcell head was simultaneously rotated and moved axially unto the powdersample at pre-determined normal stresses as the shear stresses weremeasured to calculate several parameters that include the flow function(FF) and powder cohesion (in kPa). Usually, powders of low cohesion havehigher FF and that represents better flow properties.

Example 4. Comparison of Morphology for Jet Milled and Wet Milled DMF

Two DMF lots produced by jet milling and wet milling are compared usingMalvern Instrument Morphologi G3. Images of both particles are shown inFIG. 2.

G3 morphologi analyzes morphological features of each individualparticle in the sample in term of aspect ratio, circularity, andconvexity. The results are shown in FIG. 3.

The measurement with G3 morphologi reveals that wet milled material isslightly less elongated, more circular and less edgy, as indicated byhigher aspect ratio, higher HS circularity and higher convexity values,respectively, as compared to the jet milled material. In addition, wetmilled material contained more thick particles, which was indicated bythe higher percentage of particles with intensity <80.

Example 5. Method of Preparing DMF Coated Particles 1) ExperimentalMethod

The enteric coated DMF is prepared using a Glatt GPCG-2 fluid bedgranulator with a 6′ Wurster column. Dissolution was run with USPapparatus II by the Pharmaceutical Analytical Development Departmentwith the following method.

TABLE 4 Dissolution method Method USP Apparatus II (paddle) Dissolutionmedia Acid Stage: 0.1N HCl Buffer Stage: SIF without pancreatin, pH 6.8Dissolution Volume (mL) 500 Temp (° C.) 37 ± 0.5 Rotation Speed (rpm)100 Sampling Auto Sampler: Replicate N = 2

2) Sample Preparation

DMF first de-lumped with a Frewitt Comillwith screen size 1.0 mm. Then,it is mixed with silicon dioxide (Aerosil) and being fluidize in thefluid bed granulator for 5 minutes.

TABLE 5 Powder formulation Ingredients Weight % DMF 99.5 Aerosil 200 0.5

Eudragit L100 and triethyl citrate is used for coating an enteric layerfor stomach acid protection on the DMF API particles. Samples were takenat different L100 weight gain to compare gastric protection capability.

TABLE 6 Enteric coat formulation Ingredients Weight % Eudragit L100 6.5IPA 90.7 Water 1.5 Triethyl citrate 1.3The coating parameters are as follow:

TABLE 7 Coating parameters Airflow Product temp Spray rate Atom pressure(m3/hr) (° C.) (g/min) (bar) 40 22-25 15-20 2.5

FIG. 4 shows the SEM images of uncoated DMF and enterically coated DMF.FIGS. 5 and 6 show dissolution profiles for DMF coated particles in SGFand SIF.

Example 6. Comparison of Enteric Coated DMF Using Unmilled Coarse DMFVersus Wet-Milled DMF

Unmilled coarse DMF were coated according to the method of described inExample 5. Various properties of the unmilled coarse DMF and entericallycoated DMF are compared with wet-milled DMF and enterically coated DMFmade from wet-milled DMF. See Table 8.

TABLE 8 Unmilled coarse API Wet milled API Particle size Sieve cut of130 μm D₅₀ = 60-100 μm to 350 μm Particle morphology 2D plate structure3D structure SEM of uncoated FIG. 7A FIG. 7B API particles Flow of APIparticle Uneven flow due to Smooth and in fluid bed API plate structureuniform flow Coated crystals Significant agglomeration Isolated andsmall due to uneven flow of coated particles with particles in the asmall span coating process SEM of coated API FIG. 7C FIG. 7D particles

As shown in Table 8 and FIGS. 7A-7D, unmilled coarse DMF particles arenot suitable for making the enterically coated DMF particles of thepresent invention. Significant agglomeration of the coated particles wasobserved possibly due to the 2D plate structure of the coarse DMFparticles. In contrast, wet-milled DMF particles have three dimensionalmorphology and desirable flowability, which results in small coatedparticles with uniform size distribution.

1-65. (canceled)
 66. Dimethyl fumarate (DMF) coated particles comprisingDMF starting particles coated with an enteric coating, wherein the DMFstarting particles having a volume median diameter (D₅₀) between 50 μmand 100 wherein the span ((D₉₀−D₁₀)/D₅₀) of the starting DMF particlesin the composition is in the range of 1.3 to 1.9; and wherein whensubjected to an in vitro dissolution test employing USP SimulatedGastric Fluid (SGF) without pepsin as dissolution medium, the entericcoated DMF particles release no more than 20% of DMF over 4 to 12 hours.67. The DMF coated particles of claim 66, wherein no more than 15% ofDMF is released over 4 to 12 hours.
 68. The DMF coated particles ofclaim 66, wherein the coated particles have a particle size less than500 μm.
 69. The DMF coated particles of claim 66, wherein the coatedparticles have a median diameter (D₅₀) in the range of 100 μm to 500 μmor in the range of 100 μm to 250 μm.
 70. (canceled)
 71. The DMF coatedparticles of claim 66, wherein the span ((D₉₀−D₁₀)/D₅₀) for the coatedparticles is equal to or less than 1.0.
 72. The DMF coated particles ofclaim 71, wherein the span for the coated particles is less than 0.8.73. The DMF coated particles of claim 71, wherein the span for thecoated particles is less than 0.6.
 74. The DMF coated particles of claim71, wherein the span for the coated particles is in the range of 0.5 to1.0 or 0.6-0.8.
 75. (canceled)
 76. The DMF coated particles of claim 66,wherein the weight of the enteric coating is greater than 30%, 50%, or80% of the weight of the DMF starting particles.
 77. (canceled) 78.(canceled)
 79. The DMF coated particles of claim 76, wherein the weightof the enteric coating is 30-200%, 50-150%, 80-120%, or 90-120% of theweight of the DMF starting particles. 80-82. (canceled)
 83. The DMFcoated particles of claim 66, wherein the enteric coating comprises anexcipient selected from the group consisting of a copolymer ofmethacrylic acid and methyl methacrylate, a copolymer of methacrylicacid and ethyl acrylate, hypromellose phthalate (HPMCP), celluloseacetate phthalate.
 84. The DMF coated particles of claim 83, wherein theenteric coating comprises a copolymer of methacrylic acid and methylmethacrylate.
 85. The DMF coated particles of claim 84, wherein theratio of the methacrylic acid to the methyl methacrylate in thecopolymer is 0.8:1 to 1.2:1 or 1:1 (Eudragit L100).
 86. (canceled) 87.The DMF coated particles of claim 66, wherein the enteric coatingcomprises a plasticizer.
 88. The DMF coated particles of claim 87,wherein the plasticizer is selected from the group consisting ofacetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, castoroil, chlorobutanol, diacetylated monoglycerides, dibutyl sebacate,diethyl phthalate, glycerin, mannitol, polyethylene glycol, polyethyleneglycol monomethyl ether, propylene glycol, pullulan, sorbitol, sorbitolsorbitan solution, triacetin, tributyl citrate, triethyl citrate andvitamin E.
 89. The DMF coated particles of claim 88, wherein theplasticizer is triethyl citrate.
 90. The DMF coated particles of claim89, wherein the weight ratio of the triethyl citrate to the copolymer ofmethacrylic acid and methyl methacrylate is from 1:1 to 1:20.
 91. TheDMF coated particles of claim 90, wherein weight ratio of the triethylcitrate to the copolymer of methacrylic acid and methyl methacrylate is1:5. 92-212. (canceled)
 213. A pharmaceutical composition comprising DMFcoated particles of claim
 66. 214. A method of treating multiplesclerosis in a subject in need thereof, comprising administering to thesubject an effective amount of a pharmaceutical composition of claim213.
 215. (canceled)